BACKGROUND AND OBJECTIVES: Previous research identified cognitive reappraisal as an adaptive emotion regulation strategy. However, theories on emotion regulation flexibility suggest that reappraisal effectiveness (RE) may depend on an individual's familiarity with stressors. In this study, we expect high reappraisal inventiveness (RI), i.e., the generation of many and categorically different reappraisals, to increase RE for individuals with low situational familiarity. Individuals with high situational familiarity, however, would be more effective with low RI. DESIGN: A total of 148 participants completed the Script-based Reappraisal Task, in which they were presented with fear- and anger-eliciting scripts. Depending on trial type, participants were instructed to reappraise (reappraisal-trial) or react naturally (control-trial) to the scripts. After each trial, participants indicated affective states and reappraisals. We assessed RI and calculated RE-scores as difference between affect ratings in reappraisal- and control-trials for valence and arousal. Finally, participants rated the familiarity with each situation. RESULTS: The results indicated a significant moderating effect of situational familiarity on the relationship between RI and RE-valence (not RE-arousal). The moderation was mainly driven by a detrimental effect of RI for individuals with high situational familiarity. CONCLUSIONS: Our results hint at the importance of individual experience with emotional content in the research of cognitive reappraisal.