BackgroundTeamwork in the operating room is of paramount importance to provide high-quality patient care. It has been shown that increased team member familiarity predicts improved teamwork. A complicating factor is the often-changing composition of the operating room teams. Team member familiarity is associated with shared mental models and mutual trust, which are in turn important factors for team effectiveness. However, it remains unclear how this interplay takes place and can be influenced (eg, through team training). Our aim was to investigate the relationship between team member familiarity and perceived team effectiveness in operating room teams. We hypothesized that shared mental models and mutual trust mediate this relationship. MethodsWe performed a prospective, correlational study in 2 hospitals in the Netherlands. A questionnaire was used to assess team member familiarity, mutual trust, shared mental models (perceived and content-related), and perceived team effectiveness. Data were analyzed using a random intercept multilevel model. ResultsTeam member familiarity significantly predicted perceived team effectiveness, both through a direct effect, as well as mediated by perceived shared mental models. Mutual trust also significantly predicted team effectiveness. Variance is determined mostly at an individual level, but also partly (12%) at the operating room level. ConclusionGreater team member familiarity predicts greater team effectiveness, and this relationship is mediated by shared mental models. Training should be aimed at these aspects of team functioning to optimize team performance in the operating room.