Objective. To describe the extent of adherence to the recommended neonatal zidovudine (ZDV) regimen administered to infants who have been exposed to the human immunodeficiency virus (HIV) to prevent mother-to-child transmission of HIV and to determine which maternal factors are associated with compliance. Methods. HIV-infected women (n = 87) who were participating in a larger study of perinatal transmission at 3 inner-city New York City hospitals were interviewed 2 to 6 weeks’ postpartum to assess adherence to neonatal prophylaxis, social support, social network factors, and depression. In addition, plasma samples of 45 of their infants were assayed for ZDV levels. Results. A majority of women (71%) administered all of the prescribed 4 daily doses in the previous week, as measured by interview; self-reported adherence was not associated with any maternal characteristics. In contrast, poor adherence, as measured by lower infant ZDV plasma levels, was associated with asymptomatic HIV illness in the mother and having 2 or more other children; good adherence, as indicated by higher ZDV levels, was associated with the presence of a maternal social support network, disclosure of HIV infection, and mothers’ adherence to their own ZDV regimens during pregnancy. In multivariate regression analyses, maternal asymptomatic status (β = −0.40) was associated with lower infant ZDV levels, and maternal adherence during pregnancy (β = 0.37) was associated with higher levels. Conclusions. Women who are HIV asymptomatic and lack a social support network are more likely not to comply with the recommended neonatal prophylactic regimen of antiretroviral therapy. Future studies should address the prenatal period and social network factors, such as disclosure of serostatus, and the custody of other children.