We examined socioeconomic status and social and sexual network factors and their relationship to HIV acquisition risk among HIV-negative Black MSM (BMSM), White MSM (WMSM) and transfemales (male to female transgenders). Geographic analysis examined residential patterns and neighborhood patterns of HIV prevalence in San Francisco. Factors associated with engaging in more episodes of potentially HIV serodiscordant unprotected receptive anal intercourse were analyzed. Transfemales and BMSM were more likely to live in areas of higher HIV prevalence and lower income compared to WMSM. BMSM and transfemales had lower socioeconomic scores (SES) scores compared to WMSM. BMSM were more likely to report serodiscordant partnerships and higher numbers of potentially serodiscordant unprotected sex acts. Decreasing individual SES did not predict serodiscordant partnerships in any group. Increasing neighborhood HIV prevalence predicted an increase in the number of potentially serodiscordant unprotected sex acts among transfemales and BMSM but only significantly so for transfemales. Prevention interventions must consider neighborhood HIV prevalence, and HIV prevalence in social/sexual networks, in addition to considering individual level behavior change or poverty reduction.