Association of human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 cell percent, and mortality was examined in stored sera from 254 infected children in an intravenous immunoglobulin infection prophylaxis trial. Ninety-two children (36.2%) died (41 during the study, 51 during long-term follow-up). The geometric mean baseline HIV-1 RNA level was 104,626 copies/mL, and the mean CD4 cell percent was 25%. Relative risk of death (RR) was 2.1 if the baseline RNA level was > 100,000 copies/mL (95% confidence interval [CI], 1.4–3.0) and was 3.0 if the baseline CD4 cell percent was <15% (95% CI, 2.2–4.0). If RNA levels increased after baseline, the RR was 1.8 (95% CI, 1.3–2.6), and if the CD4 cell percent dropped to <15%, the RR was 2.8 (95% CI, 1.6–4.9). In a multivariate model, both baseline RNA level and CD4 cell percent were independently associated with mortality risk. In a time-dependent model, the RR per log10 increase in HIV-1 RNA copy numbers was 2.8 (95% CI, 2.1–3.6) and per 5 percentage point decrement in CD4 cell percent was 1.3 (95% CI, 1.2–1.5). Both variables should be considered for in decision-making regarding therapy and evaluation of antiretroviral response.