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Veterans with posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), the 2 most prevalent mental health disorders in the Iraq and Afghanistan veterans, are at increased risk for cannabis use and problems including cannabis use disorder (CUD). The present study examined the relationship of PTSD and MDD with cannabis use frequency, cannabis problems, and CUD as well as the role of 3 coping-oriented cannabis use motives (coping with negative affect, situational anxiety, and sleep) that might underlie this relationship. Participants were veterans (N = 301) deployed post-9/11/2001 recruited from a Veterans Health Administration facility in the Northeast United States based on self-reported lifetime cannabis use. There were strong unique associations between PTSD and MDD and cannabis use frequency, cannabis problems, and CUD. Mediation analyses revealed the 3 motives accounted, in part, for the relationship between PTSD and MDD with 3 outcomes in all cases but for PTSD with cannabis problems. When modeled concurrently, sleep motives, but not situational anxiety or coping with negative affect motives, significantly mediated the association between PTSD and MDD with use. Together with coping motives, sleep motives also fully mediated the effects of PTSD and MDD on CUD and in part the effect of MDD on cannabis problems. Findings indicate the important role of certain motives for better understanding the relation between PTSD and MDD with cannabis use and misuse. Future work is needed to explore the clinical utility in targeting specific cannabis use motives in the context of clinical care for mental health and CUD.