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 copy of the TAT haplotype reduced the odds of MDE by almost 40% (OR = 0.63). In AA women without an ACE and two TAT haplotypes, the risk of MDE was increased (OR = 1.51 for each copy). Our findings in relation to the TAT haplotype of CRHR1 extend those obtained in other populations to a largely substance-dependent one. The complex structure of CRHR1 may help to explain why some variants in the gene moderate the effects of an ACE only on depression risk while others moderate the effect of an ACE only on AD risk. © 2011 Wiley Periodicals, Inc.