Zidovudine prophylaxis is recommended to reduce perinatal HIV-1 transmission, but there are limited data on long-term effects on women's health. Pediatrics AIDS Clinical Trials Group (PACTG) 288 was a prospective observational study among US women randomized to zidovudine or placebo in PACTG 076 that was designed to evaluate and compare postpartum clinical, immune, and viral parameters between randomized treatment arms. Forty-eight percent (226/474) of eligible women enrolled in the study (mean follow-up of 4.1 years). Progression and time to AIDS or death were similar in both groups, observed in 21 (19%) zidovudine group women and 29 (25%) placebo group women (RR = 0.73, 90% CI: 0.46-1.17). No significant differences in CD4 lymphocyte count or HIV RNA levels were detected. Genotypic zidovudine resistance was detected in 10% of 156 women (9% of zidovudine group women and 11% of placebo group women). Based on our data, ZDV monotherapy could be considered as chemoprophylaxis to reduce perinatal HIV transmission for minimally symptomatic HIV-infected pregnant women with a low viral load and normal CD4 cell count who do not want to receive highly active antiretroviral therapy because of concern about potential side effects or who wish to reduce fetal exposure to multiple drugs during pregnancy.