This study examined overall and gender-specific associations between place-based characteristics and opposite-sex exchange sex among people who inject drugs (PWID) in the U.S. PWID were recruited from 19 metropolitan statistical areas (MSAs) for the Centers for Disease Control and Prevention’s 2012 National HIV Behavioral Surveillance. Administrative data were used to describe the economic, social, and political features of the ZIP codes, MSAs, counties, and states where PWID lived. Multilevel modeling estimated associations of place characteristics and exchange sex. We found that 52% of women and 23% of men reported past-year opposite-sex exchange sex (N = 7599). Female PWID living in states with stronger policies supporting working caregivers had lower odds of exchange sex (aOR = 0.80; 95% CI 0.69, 0.94). PWID living in ZIP codes with greater economic deprivation had higher odds of exchange sex (aOR = 1.10; 95% CI 1.03, 1.17). We found that a high percentage of male PWID exchanged sex with women; determinants and risks of this group merit exploration. If future research establishes that the relationships identified here are causal, interventions to reduce exchange sex among PWID should include policies supporting working caregivers and reducing poverty rates.