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Adverse childhood experiences (ACEs) increase the risk for adult depression and substance dependence, possibly mediated by the corticotropin‐releasing hormone type 1 receptor (CRHR1). In some studies, a three‐SNP “T‐A‐T” haplotype in CRHR1, which encodes CRHR1, exerted a protective moderating effect on risk of depression in adults with ACEs. Other studies have shown a main or moderating effect of SNPs in CRHR1 on alcohol consumption. We tested the moderating effects of the three‐SNP haplotype on lifetime risk of a major depressive episode (MDE) and alcohol dependence (AD) in 1,211 European‐Americans (EAs) and 1,869 African‐Americans (AAs), most of whom had a lifetime substance use disorder. There were no significant main or interaction effects of the TAT haplotype on AD. There was a significant interaction of ACE by TAT on risk of depression only in AA women (P = 0.005); each …