Interleukin (IL)-10 directly inhibits human immunodeficiency virus type 1 (HIV-1) replication, but it may also promote viral persistence by inactivation of effector immune mechanisms. Here, we show in an African cohort that individuals with genotypes associated with high IL-10 production at 2 promoter single-nucleotide polymorphisms (-1082 and -592) were less likely to become HIV-1 infected but had significantly higher median plasma viral loads during the acute phase (<or=3 months after infection). However, as the infection progressed, the association between genotype and median viral load was reversed. Thus, IL-10 may influence HIV-1 susceptibility and pathogenesis, but effects on the latter may differ according to the infection phase.