This study compared rural and urban crack-using women and examined their responses to two interventions. A prospective cohort study design was employed to assess the effectiveness of standard and innovative HIV prevention interventions on 541 urban and 268 rural women in Florida. Generalized estimating equation analysis, accounting for repeated measures, found that for combined urban and rural samples, the innovative intervention was more effective than the standard for a number of drug and sexual risk behaviors. However, the analysis indicated no significant differences in intervention efficacy between rural and urban women. The results imply that there is a need for similar HIV prevention services in both areas.