OBJECTIVE: We investigated the effect of descent (African versus European) on the progression of untreated HIV infections in a prospective cohort study of HIV-1-infected individuals. METHODS: We estimated the linear rate of decline of the CD4 cell count and the setpoint viral load in patients with sufficient data points. The effect of descent was assessed by microltivariate regression models including descent, sex, viral subtype, the earliest date of confirmed infection, age, and the baseline CD4 cell count; the rate of CD4 cell count decline was also analyzed with mixed-effect models and with matched comparisons between patients of African and European descent based on the baseline CD4 cell count. RESULTS: We found that the decline slope of the CD4 cell count was significantly less steep (+26.6 cells/microl per year; 95% confidence interval, 12.3-41.0; P < 0.001) in patients of African descent (n = 123) compared with patients of European descent (n = 463), and this effect was independent of differences in the infecting viral subtypes. Matched comparisons confirmed the effect of African descent (P < 0.001). Remarkably, the rate of CD4 cell count decline depended strongly on the viral setpoint in patients of European descent (-46.3 cells/microl per year/log10 RNA copies/ml; 95% confidence interval, -55.8 to -36.7; P < 0.001) but not in patients of African descent. CONCLUSION: Slower disease progression in patients of African descent might be related to host factors allowing better tolerance of high virus levels in patients of African descent compared with patients of European descent.