Background. Antiretroviral (ARV) prophylaxis effectively reduces mother-to-child transmission of human immunodeficiency virus type 1 (HIV). However, it is unclear whether stopping ARVs after breastfeeding cessation affects maternal HIV disease progression. We assessed 18-24-month postpartum disease progression risk among women in a randomized trial assessing efficacy and safety of prophylactic maternal ARVs. Methods. From 2005 to 2008, HIV-infected pregnant women with CD4 + counts of 200-500/mm 3 were randomized to receive either triple ARV (zidovudine, lamivudine, and lopinavir/ritonavir during pregnancy and breastfeeding) or AZT/sdNVP (zidovudine until delivery with single-dose nevirapine without postpartum prophylaxis). Maternal disease progression was defined as the combined endpoint of death, World Health Organization clinical stage 4 disease, or CD4 + counts of <200/mm 3.Results.Among 824 randomized women, 789 had at least 1 study visit after cessation of ARV prophylaxis. Following delivery, progression risk up to 24 months postpartum in the triple ARV arm was significantly lower than in the AZT/sdNVP arm (15.7 vs 28.3; P =. 001), but the risks of progression after cessation of ARV prophylaxis (rather than after delivery) were not different (15.0 vs 13.8 18 months after ARV cessation). Among women with CD4 + counts of 200-349/mm 3 at enrollment, 24.0 (95 confidence interval [CI], 15.7-35.5) progressed with triple ARV, and 23.0 (95 CI, 17.8-29.5) progressed with AZT/sdNVP, whereas few women in either arm (<5) with initial CD4 + counts of ≥350/mm 3 progressed. Conclusions. Interrupting prolonged triple ARV prophylaxis had no effect on HIV progression following cessation (compared with AZT/sdNVP). However, women on triple ARV prophylaxis had lower progression risk during the time on triple ARV. Given the high rate of progression among women with CD4 + cells of <350/mm 3, ARVs should not be discontinued in this group.Clinical Trials Registration.ISRCTN71468410.