Nihilism pervades the universe of the Fallout Series on a metaphysical level.  This is a marked separation from the theistic metaphysics of traditional American RPG, which is embodied by the Dungeon & Dragons family of games (both pencil & paper and VG incarnations).  The differences might be summed up by simply stating that one is a Fantasy RPG, while the other is a Post-Apocalyptic RPG.  Given that a hypothetical (and some actual) RPG(s) do blend such sub-genres, a more detailed discussion is in order.    

D&D is a universe of planes and deities.  The reality which player characters can experience is not limited to a single plane/dimension: without bogging the discussion down with specifics, the player character or party (group of player characters) can travel to a number of different dimensions (based on their levels and abilities).  

Further, the player character can affect and is affected by different planes even when centered on an entirely different plane.  As an example, a spellcast might call forth a creature or even force of nature from another plane, or it might banish an enemy to another plane; depending on the complexity of a campaign, the party might be forced to travel as a group to a different plane (or several) in order to rescue a party member or as a major plot point.  The multiplicity of planes gives players access to a variety of powers and abilities.   

Beyond the blended reality of D&D games, the metaphysics of D&D contains deities.  The system of deities is quite complex, with Elemental Gods, demiurges, demigods and so on.

The historiography & cosmogony of D&D indicate that specific deities have control over certain realms, planes, and forces.  Player characters are most often bound to one of these Gods, granting the player special bonuses and abilities: penalties may be instituted for straying from the player's deity's path.

The Deities, just like player characters, are placed somewhere on the biaxial Alignment Grid: Good/Evil & Order/Chaos, where Neutrality is the center between these opposites.  Deities can thus be Lawful Good, Chaotic Neutral, Neutral Evil, etc.  [I know that D&Dophiles will get upset with these gross generalizations, but I think they are acceptable for the discussion at hand]

RPGs of Asian origin are often quite similar to the D&D system in their metaphysics; a major difference often arises from the lack of specific deities.  Instead a pervasive Spirit sustains the world; in these games,the Spirit may have 'good', 'evil', and 'neutral' incarnations, but ultimately they all serve the same goal: balance in the universe.  In theistic universes, the player has a guiding set of principles, which are predetermined; these principles constitute a context for moral choice.  

Whether following the ethos of their personal deity, or seeking to achieve universal balance, choices are more or less clearly defined as either advancing or obstructing the goals of the player. These goals themselves are dictated by the moral structure imposed through the narrative.  Any moral ambiguity that exists is due to the relative clarity of connections between choice and consequence.

The Fallout series, by contrast, has no *controlling* deities and has a single plane of existence. Players can never find themselves within a different or separated world (the Matrix-like dream world within Fallout 3 is merely a subset of the existing physical reality, not a separate plane); with only a single plane of existence, all aggressive are final: spirits of NPCs, friend and foe alike, are not recoverable nor is death reversible.  Short of a reload, death (for any character) is truly terminal. 

This is quite different than D&D and all similar universes, wherein the player may resurrect friends and opponents, or speak to their spirits, in order to further a plot temporarily halted by an unfortunate death (in VGs this realm of action is obviously more limited than a tabletop where a GM has flexibility).  The single plane of existence basically means that what a player sees is what they get:  magical and spiritual powers are nowhere to be found.

While historical religions are referenced, and even a few post-Apocalyptic new religions are present (i.e. the Children of Atom), there is no controlling deity: that is, no deity will intervene on the player's behalf, or act against the player based on the player's decision making or alignment.  

An important point:  Fallout lacks the biaxial Alignment grid ofD&D, instead relying on the Karmic system, wherein good deeds gain Karma, and evil deeds lose Karma.  Here there is obviously no preset moral framework; instead, the player must choose how they wish to be perceived by the inhabitants of such a desolate world, and act accordingly.  Moral ambiguity is part and parcel of the Fallout universe.

Morality is humanistic within the Fallout series, and theistic within the D&D universe (even neutrality is a religio-social choice in D&D).  In Fallout 3, no god commands evil behavior from evil characters, it is the player who chooses to be evil or good.  While Neutral Neutral PCs in the D&D universe closely approximate this, there is still a difference in that deities can still aid and deter the NN PC.  

D&D and Fallout would be polar opposites if charted on a continuum, axis, or biaxial grid.  The differences in metaphysics between the two systems can be summed up by the ways in which the systems restrict and license actions: D&D allows for more freedom of physical action, and less freedom in moral choice; Fallout allows for fewer physical actions, yet gives more freedom to moral choice. 

During the design phase, the metaphysical underpinnings of the game world should be of paramount importance in discussion and decision making.  It is possible to blend systems like D&D and Fallout to provide broad license within both the physical and moral realms, or to tightly restrict both; game mechanics and narrative structure have a common foundation in the solution of this specific issue. Ignoring this aspect will lead to a game world that has (possibly serious) immersion problems.