In psychopathologies characterized by compulsive decision-making, core impairments include cognitive inflexibility and excessive sensitivity to rewards. It has been posited that traits shared by nonclinical individuals and psychiatric patients could help explain the pathogenesis of compulsive decision-making. To investigate whether cognitive inflexibility predisposes nonclinical individuals to poor choices and hyper-reactivity to reward, we recruited people with high and low scores for cognitive persistence and used the Iowa Gambling Task to assess decision-making and cardiac reactivity to monetary gains/losses. As is frequently observed in psychophysiological research, the data indicated discrepancies among self-reports, behavior, and physiology. Cognitive inflexibility was not related to worse performance; however, monetary gains, in line with the literature, prompted marked cardiac accelerations. Consistent with our research goal, only inflexible participants showed large cardiac accelerations during the largest monetary wins. Taken together, the data confirm an association between cognitive persistence and physiological reward sensitivity in a nonclinical population. The findings are in line with recent theories on the development of compulsive behaviors that consider cognitive inflexibility as a transdiagnostic impairment and predisposing factor for excessive reactivity to rewards, and might act both as a preexisting individual trait and drug-induced deficit.