Abstract The current cross-sectional study examined psychological inflexibility, a process in which behavior is rigidly guided by psychological reactions rather than direct contingencies or personal values, as a transdiagnostic process relevant to a range of depressive, anxiety, substance use and eating disorders. A sample of 972 first-year college students between 17 and 20 years of age completed self-report measures of psychological inflexibility and psychological distress as well as a structured diagnostic interview. Psychological inflexibility was significantly higher across a range of current and lifetime depressive and anxiety disorders as well as lifetime history of eating disorders, relative to students with no disorder, even after controlling for general psychological distress. Findings were mixed for substance use disorders, with a more consistent pattern for lifetime history than for current disorders. Psychological inflexibility was also related to having comorbid depressive, anxiety, and substance use disorders relative to only having one of these diagnoses. Results are discussed in relation to research on psychological inflexibility as a transdiagnostic pathological process and target for interventions.