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Despite the increased prevalence of weight discrimination, few studies have examined the association between perceived weight discrimination and the prevalence of current psychiatric disorders in the general population. This study utilized a subsample of overweight and obese individuals (N = 22,231) from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a cross-sectional nationally representative study of noninstitutionalized US adults. Perceived weight discrimination is associated with substantial psychiatric morbidity and comorbidity. These results remained significant after adjusting for a potential confound, perceived stress. Moreover, social support did not buffer against the adverse effects of perceived weight discrimination on mental health. Controlling for BMI did not diminish the associations, indicating that perceived weight discrimination is potentially harmful to mental health regardless of weight. These results highlight the urgent need for a multifaceted approach to address this important public health issue, including interventions to assist overweight individuals in coping with the mental health sequelae of perceived weight discrimination.