A community-based study of human immunodeficiency virus type 2 (HIV-2) infection was conducted in a rural village in northern Guinea Bissau, West Africa to assess the relationship between plasma HIV-2 RNA levels, CD4 lymphocyte percentage, and survival over an 8-year period. The cohort of 133 HIV-2-infected individuals and 160 HIV-uninfected controls enrolled in 1991 were followed up at home until 1998. Thirty-one (23%) HIV-2-infected and 24 (16%) HIV-uninfected individuals died over the follow-up period (mortality hazard ratio 1.7, 95% CI 1.0, 2.9; p= 0.06). In HIV-2-infected individuals, the median HIV-2 RNA level was 347 copies/ml and the mean CD4% was 28.6. Both plasma viremia and CD4% were independent predictors of survival, with hazard ratios increasing by 1.6 (95% CI, 1.1, 2.3) for each log₁₀ increase of plasma viremia and 1.7 (1.1, 2.6) for each 10% decrease of CD4%. Infected subjects with a plasma viral load ≥ the median (347 copies/ml) and a CD4% ≤ the mean (28.6%) had a mortality hazard ratio of 3.1 (95% CI 1.7, 5.8) compared to uninfected controls, whereas the remaining infected subjects had a mortality rate similar to uninfected controls, the mortality hazard ratio being 1.0 (95% CI, 0.5, 2.1.) In those who survived between 1991 and 1996, HIV-2 RNA levels were unchanged overall and CD4 lymphocyte counts remained high. In conclusion, baseline HIV-2 RNA levels predicted a normal survival for the majority, with low and stable levels of plasma viremia characterizing HIV-2 infections in this rural West African community.