This study examined the co-occurrence of cocaine, alcohol, marijuana, and other drug use among treatment seeking homeless persons to determine whether alcohol use predicted cocaine use differently than marijuana and other drugs predicted cocaine use. Participants were 141 homeless persons with substance use and other nonpsychotic mental disorders seeking drug treatment at a metropolitan health care agency for homeless persons. They were 72.3% male, 27.7% female, 82.7% African American, 17.3% Caucasian, with an average age of 37.7 (SD 7.1) years and had 13.1 (SD 2.4) average years of education. Results supported the assertion that cocaine use was strongly associated with extent of alcohol use and that the association between cocaine and alcohol was stronger than the association between cocaine and other drug use, including marijuana. Participants with cocaine plus alcohol disorders were retained longer in treatment than disorders of cocaine only with no differences in abstinence outcome. The findings should drive further research into the use of alcohol as a trigger or predictor of cocaine use, the deleterious effects of the combined use of cocaine and alcohol, and specialized treatments for polysubstance users.