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Objectives: To evaluate clinical conditions associated with mortality in HIV-infected children with CD4+ counts <100 cells/microl., Methods: The Pediatric Spectrum of HIV Disease Project is a longitudinal medical record review study with eight study sites in the United States, which have been enrolling children since 1989. Survival time from baseline very low CD4 count (<100 cells/microl) to death was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to evaluate the effect of clinical variables on mortality., Results: Of 522 children (>/=1 year of age) with serial CD4+ T-lymphocyte measurements, the median age at the first very low CD4 count was 4.8 years. The estimated median survival following the first very low CD4 count was 36 months. The following factors present at the first very low CD4 count were independently associated with a higher risk of death: younger age, weight-for-age >2 standard deviations below the mean, and previously diagnosed AIDS. The subsequent development of cytomegalovirus (CMV)-associated disease, Mycobacterium avium intracellulare (MAI) infection, wasting syndrome, or esophageal candidiasis was also independently associated with a higher risk of death., Conclusion: Survival in HIV-infected children with very low CD4 counts before introduction of highly active antiretroviral therapy was highly variable. Poor nutritional status and the development of CMV disease or MAI infection were associated with the shortest survival times.