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In Vs System 2PCG, players choose a main character, build a deck with exactly sixty cards, and attempt to KO the other player's main character in a game of superhero battles.

Vs System 2PCG is superficially similar to the original Vs. System collectible card game, but is a completely rebuilt game that takes some inspiration from the original. Combat has been streamlined, the turn structure is different, the resource system has been revamped, and the game is no longer collectible, with cards instead being released in a non-random format. A single box contains a full play-set of all cards.

Vs System 2PCG: SHIELD vs Hydra pits these two organizations against each other with 200 new cards including Main Characters, Supporting Characters, Plot Twists, and Locations. Vs System 2PCG: SHIELD vs Hydra can be combined with any other Vs System 2PCG sets.