We analyzed T-cell responses to mitogens and antigens and B-cell differentiation in response to T-cell dependent (TCD) and independent stimuli in 22 human immunodeficiency virus (HIV)-infected children (1 to 9 years of age) according to the presence of protective humoral immunity at a mean time of 18 months after vaccination with Haemophilus influenzae type b, hepatitis B, diphtheria, and tetanus vaccines. The 17 vaccine responders had a mean of 3.2 responses. However, their antibody levels were lower compared with healthy children. The 5 nonresponders had a mean of 0.84 responses. There were no significant differences between responders and nonresponders regarding age, Centers for Disease Control and Prevention (CDC) disease class, CDC immunologic class, serum immunoglobulin (Ig) levels, or in the use of antiretroviral therapy. However, responders tended to have higher age-adjusted absolute CD4 cell counts than nonresponders (p = 0.07). Nonetheless, there was no correlation between antibody levels and age-adjusted CD4 counts for each of the 4 TCD vaccines. Responders had conserved lymphoproliferative responses to mitogens and to candida antigen; 7 (41%) had normal responses to tetanus antigen. While nonresponders had some conserved responses to mitogens, only 1 had a response to antigen. Thirteen responders (77%) and only 1 nonresponder (20%) had normal responses to at least 2 of the 3 mitogens and 1 of the 2 antigens (p = 0.04). Although defects in B-cell differentiation were detected in both groups, they were profound and generalized in the nonresponders. Fourteen responders (82%) had at least 1 normal B-cell response compared with none of the 5 nonresponders (p = 0.002). There were no correlations between normal lymphoproliferative responses and age, CD4 counts, serum immunoglobulin G (IgG) levels, or the use of antiretroviral therapy. Immunologic function is important in the evaluation of HIV-infected children.