Preliminary evidence suggests that a CD4 cell count < 50 cells/mm3 is associated with a particularly poor short-term prognosis, and is both necessary and sufficient for death associated with HIV infection. We sought to validate these findings in a cohort of 1,415 zidovudine (ZDV)-treated patients, with advanced HIV infection, and to examine more closely the profile of CD4 cell decline over the 2 years prior to death. As of December 31, 1991, 432 patients had died. The cumulative 2 year survival of patients once their CD4 cell count fell to < or = 50 cells/mm3 (median survival = 17.3 months) was substantially shorter at 25.7%, than from when their CD4 cell counts first fell within the range 51-100/mm3 (51.4%); 101-150/mm3 (67.3%); or 151-200/mm3 (76.5%). The percent of patients with a CD4 count < 50 cells/mm3, increased from 33% at 24 months prior to death to 58% at 12 months and 86% at 1 month. Patients with a CD4 count > or = 50 cells/mm3 in the month prior to death, were significantly older (p < 0.001) and had higher CD4 cell counts (p < 0.05) at initiation of ZDV compared to those with a CD4 count < 50 cells/mm3. There were no important differences in HIV risk category, duration of ZDV therapy or use of PCP prophylaxis between the two groups. These findings highlight the importance of more intensive monitoring of patients with CD4 counts < 50 cells/mm3, since life-threatening opportunistic infections are more likely to supervene at this stage. A CD4 count < 50 may also be a useful surrogate endpoint for survival in clinical trials.