Human immunodeficiency virus (HIV)‐negative infants born to HIV‐positive mothers frequently exhibit a range of immunological abnormalities. We tested the hypothesis that HIV during pregnancy affects the ability of CD4 T cells of HIV‐negative infants to respond to vaccine challenge by recruiting HIV‐negative infants born to HIV‐negative and HIV‐positive mothers and measuring their responses to Bacille Calmette‐Guérin (BCG) vaccine given at birth. At 2 weeks, maternal HIV status did not influence CD4 T‐cell counts or differentiation, but by 10 weeks CD4 counts of infants born to HIV‐positive mothers fell to a level characteristic of HIV‐positive infants. Among the CD4 T‐cell populations, markers of differentiation (CCR7⁻ CD45RA⁻ CD27⁻) and senescence (CD57, PD‐1) were more common among infants born to HIV‐positive mothers than among infants born to HIV‐negative mothers. At 2 weeks of age, we assessed the effector response to heat‐killed BCG and tuberculin purified protein derivative (PPD) by overnight interferon (IFN)‐γ enzyme‐linked immunosorbent spot‐forming cell assay (ELISpot), but found no measurable effect of maternal HIV status. At 10 weeks, we assessed CD4 T‐cell memory by measuring proliferation in response to the same antigens. We observed a bimodal response that allowed infants to be classified as high or low responders and found that fewer infants born to HIV‐positive mothers were able to mount a robust proliferative response, suggesting that their reduced CD4 counts and increased differentiation indicated a deficiency in their ability to develop immunological memory.