Despite recent surveys reporting a decline in adolescents' use of alcohol and other drugs in the general population, substance abuse may actually be increasing among particular subgroups of high-risk youth. This study examined the prevalence of alcohol and other drug use reported by 1121 youth, ages 12–24 years, seen for an initial medical visit at a free community-based primary health clinic. The clinic, located in the Hollywood/Wilshire area of Los Angeles, serves both homeless (62%) and non-homeless (38%) youth. Bivariate and multivariate analyses revealed that the homeless youth were significantly more likely to report use of alcohol and illicit drugs (marijuana, stimulants, hallucinogens, and narcotics) and prior involvement in injecting drug use (IDU). Variables found to be significantly associated with substance use among the homeless youth included length of time homeless, an attempted suicide, physical and sexual abuse, and involvement in survival sex/prostitution. Among the non-homeless youth, age of first intercourse, a previous suicide attempt, and a history of physical and sexual abuse were significantly associated with substance use. These findings suggest that rates of alcohol and other drug use may be higher among youth seen at community-based primary health clinics, particularly homeless youth underscoring the need for screening for these risk variables.