A prospective study was conducted in the Bronx, New York, of 70 infants of human immunodeficiency virus (HIV)-infected (n = 33) and uninfected (n = 37) mothers who had a history of intravenous drug use or of intravenous drug-using sex partners. Infants were observed from birth to a median age of 23 months (range 3 to 54 months). HIV infection was confirmed in seven infants (21%) of seropositive mothers; six developed HIV disease, with symptoms observed in the first year. Of these, three died (3, 9, and 36 months) of HIV-related causes; 3 of 4 survivors were greater than 25 months of age. HIV symptoms preceded or were concurrent with abnormalities in T-lymphocyte subsets; postneonatal polymerase chain reaction confirmed HIV infection in five infants with symptoms and one without symptoms. Among infants of seropositive mothers, seven without laboratory evidence of HIV (including polymerase chain reaction) had findings suggestive of HIV infection, including persistent generalized lymphadenopathy, hepatosplenomegaly, oral candidiasis, parotitis, and inverted T-lymphocyte ratios. These findings were not observed in infants of seronegative mothers. Although the presence of HIV proviral sequences was associated with HIV disease, the observation of indeterminate symptoms in at-risk infants indicates the importance of long-term clinical follow-up to exclude HIV infection. Disease manifestations in comparable infants of seronegative mothers are important for assessment of the impact of maternal drug use, development of specific clinical criteria for early diagnosis of HIV and eligibility for antiretroviral therapy.