Modern video games represent highly advanced virtual reality simulations and often contain virtual violence. In a significant amount of young males, playing video games is a quotidian activity, making it an almost natural behavior. Recordings of brain activation with functional magnetic resonance imaging (fMRI) during gameplay may reflect neuronal correlates of real-life behavior. We recorded 13 experienced gamers (18–26 years; average 14 hrs/week playing) while playing a violent first-person shooter game (a violent computer game played in self-perspective) by means of distortion and dephasing reduced fMRI (3 T; single-shot triple-echo echo-planar imaging [EPI]). Content analysis of the video and sound with 100 ms time resolution achieved relevant behavioral variables. These variables explained significant signal variance across large distributed networks. Occurrence of violent scenes revealed significant neuronal correlates in an event-related design. Activation of dorsal and deactivation of rostral anterior cingulate and amygdala characterized the mid-frontal pattern related to virtual violence. Statistics and effect sizes can be considered large at these areas. Optimized imaging strategies allowed for single-subject and for single-trial analysis with good image quality at basal brain structures. We propose that virtual environments can be used to study neuronal processes involved in semi-naturalistic behavior as determined by content analysis. Importantly, the activation pattern reflects brain-environment interactions rather than stimulus responses as observed in classical experimental designs. We relate our findings to the general discussion on social effects of playing first-person shooter games. Hum Brain Mapp, 2006. © 2006 Wiley-Liss, Inc.