BACKGROUND: Few population-based multilevel studies have quantified the risks that social context poses in rural communities with high HIV incidence across South Africa. We investigated the individual, social, and community challenges to HIV acquisition risk in areas with high and low incidence of HIV infection (hotspots/coldspots). METHODS: The cohort (N = 17,376) included all HIV-negative adults enrolled in a population-based HIV surveillance study from 2004 to 2015 in a rural South African community with large labor migrancy. Multilevel survival models were fitted to examine the social determinants (ie, neighborhood migration intensity), community traits (ie, HIV prevalence), and individual determinants of HIV acquisition risk in identified hotspots/coldspots. RESULTS: The HIV acquisition risk (adjusted hazard ratio [aHR] = 1.05, 95% confidence interval [CI]: 1.01 to 1.09) was greater in hotspots with higher neighborhood migration intensity among men. In women, higher neighborhood migration intensity (aHR = 1.02, 95% CI: 1.01 to 1.02) was associated with a greater HIV acquisition risk, irrespective of whether they lived in hotspot/coldspot communities. HIV acquisition risk was greater in communities with a higher prevalence of HIV in both men (aHR = 1.07, 95% CI: 1.03 to 1.12) and women (aHR = 1.03, 95% CI: 1.01 to 1.05), irrespective of hotspot/coldspot locations. CONCLUSION: HIV acquisition risk was strongly influenced by gender (ie, young women), behavior (ie, sexual debut, contraception, circumcision), and social determinants. Certain challenges (ie, community disease prevalence) for HIV acquisition risk impacted both sexes, regardless of residence in hotspot/coldspot communities, whereas social determinants (ie, neighborhood migration intensity) were pronounced in hotspots among men. Future intervention scale-up requires addressing the social context that contributes to HIV acquisition risk in rural areas with high migration.