The objective of this study is to evaluate differential response to disulfiram treatment of cocaine dependence by sex. Sex by treatment interactions from two pooled randomized clinical trials involving 191 cocaine-dependent subjects (36% female) were evaluated. Primary outcomes were days of abstinence and percentage of drug-free urine specimens. Significant sex by treatment interactions were found, where men treated with disulfiram had better outcomes than those who were not. Women had an intermediate outcome regardless of whether they received disulfiram. Sex differences in response to disulfiram treatment have important clinical and theoretical implications. Reasons for this apparent sex-based response are not clear, but possible mechanisms worthy of greater study include differences in alcohol use by sex as well as differences in dopamine-mediated responses to cocaine and disulfiram.