In Vs System 2PCG, players select a main character, construct a sixty-card deck, and aim to incapacitate the opponent's main character in superhero combat. The initial set features characters exclusively from the Marvel Universe, though future expansions may incorporate other intellectual properties.

Vs System 2PCG retains some similarities to the original Vs. System collectible card game but has been entirely rebuilt. Combat mechanics are streamlined, turn structure is altered, the resource system is redesigned, and the game is now non-collectible, with cards released in fixed sets. Each box includes a complete play-set of all cards.

Vs System: The Defenders showcases the Marvel Universe's loosely affiliated superhero "non-team" confronting the Underworld.