Although region and neighborhood condition's effect on HIV/sexually transmitted infection (STI) risk has been studied separately, there is little research examining their interplay. African American adolescents (n = 1,602) from four matched cities in the Northeastern and Southeastern US completed Audio Computer Assisted Self-Interviews and submitted biospecimen samples to detect Sexually Transmitted Infections (chlamydia, gonorrhea, and trichomonas). Logistic and negative binomial regressions determined HIV/STI risk differences by region, neighborhood stress, and stress-region dyads. Northeastern participants demonstrated lower HIV/STI risk while participants from higher stress neighborhoods exhibited greater risk. Relationships between neighborhood condition and ever having anal sex (p < 0.01), anal condom use (p < 0.05), and number of anal partners (p < 0.05) were significant in the Northeast only. Participants in unstressed Northeastern neighborhoods were less likely to have vaginal sex than those in comparable Southeastern neighborhoods (p < 0.05). Participants in unfavorable Northeastern neighborhoods had fewer anal partners than participants in comparable Southeastern neighborhoods (p < 0.01). In concert, neighborhood and region differentially affect HIV/STI risk.