Previous studies of the association of the C17T polymorphism of the mu opiate receptor gene with substance dependence compared cases with substance dependence to controls and usually found no significant association. However, the studies were limited by small sample size—no study had more than 12 subjects with the TT genotype, a genotype that is rare in white and Asian subjects. Moreover, drug use is not dichotomous but follows a spectrum from non-use to modest, intermittent use, to use several times daily. We asked whether the Kreek–McHugh–Schluger–Kellogg (KMSK) scales for alcohol, cocaine, opiates and tobacco that quantify substance use during the time of a subject's maximal use might be more sensitive measures than dichotomous outcomes. We administered the KMSK scales and completed C17T genotyping on 1009 human immunodeficiency virus (HIV)-infected and 469 HIV-uninfected women in The Women's Interagency HIV Study, an ongoing study of HIV in women. Forty-two of the 697 African American, 1 of the 182 Hispanic and none of the 161 white women had the TT genotype. KMSK cocaine, alcohol and tobacco scores were significantly higher in the African American women with the TT genotype (P = 0.008, 0.0001, and 0.006, respectively), but opiate scores were not. Ordinal regression models controlling for HIV serostatus, age, education, and income had odds ratios for the TT genotype for predicting alcohol, tobacco, cocaine and opiates scores of 2.1 (P = 0.02), 2.4 (P = 0.0004), 2.0 (P = 0.03) and 1.9 (P = 0.07). We conclude that the TT genotype of OPRM1 may increase the risk of substance use and abuse.