Homeless, substance-dependent men who have sex with men (MSM) continue to suffer health disparities, including high rates of HIV. One-hundred and thirty one homeless, substance-dependent MSM were randomized into a contingency management (CM) intervention to increase substance abstinence and health-promoting behaviors. Participants were recruited from a community-based, health education/risk reduction HIV prevention program and the research activities were also conducted at the community site. Secondary analyses were conducted to identify and characterize treatment responders (defined as participants in a contingency management intervention who scored at or above the median on three primary outcomes). Treatment responders were more likely to be Caucasian/White (p < .05), report fewer years of lifetime methamphetamine, cocaine, and polysubstance use (p < or = .05), and report more recent sexual partners and high-risk sexual behaviors than nonresponders (p < .05). The application of evidence-based interventions continues to be a public health priority, especially in the effort to implement effective interventions for use in community settings. The identification of both treatment responders and nonresponders is important for intervention development tailored to specific populations, both in service programs and research studies, to optimize outcomes among highly impacted populations.