Background and aims: A paucity of studies has examined the association between gambling and pain interference. We examined differences in the associations of gambling problem severity and psychiatric disorders among a nationally representative sample of adults with varying levels of pain interference. Methods: Chi-square tests and logistic regression analyses were performed on National Epidemiologic Survey on Alcohol and Related Conditions data from 41,987 adult respondents (48% men; 52% women), who were categorized according to two levels of pain interference (i.e., no or low pain interference [NLPI] or moderate or severe pain interference [MSPI]) and three levels of gambling problem severity (i.e., non-gamblers or low-frequency gamblers [NG], low-risk or at-risk gamblers [LRG], and problem or pathological gamblers [PPG]). Results: MSPI respondents exhibited higher rates of PPG than NLPI respondents. Categories of Axis I disorders and clusters of mood, anxiety and substance-use disorders showed similarly strong associations with problem-gambling severity in MSPI and NLPI groups. Similarly strong associations between Axis II disorders (and each cluster-A, B and C) and problem-gambling severity were also observed in MSPI and NLPI groups. Exploratory analyses suggested potentially stronger relationships between PPG and dysthymia, panic disorder, and dependent personality disorder and LRG and specific phobia in NLPI compared to MSPI respondents. Discussion and conclusions: While MSPI is associated with PPG, largely similar patterns of associations across pain-interference levels were observed between problem-gambling severity and Axis I and Axis II psychiatric disorders.