OBJECTIVE: To evaluate the effect of protease inhibitors on lipid and lactate levels and gastrointestinal symptoms in pregnancy. METHODS: Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) A5084 was an observational cohort study of human immunodeficiency virus (HIV)-infected pregnant women. Women recruited between 20 and 34 weeks of gestation were required to be on a stable, highly active antiretroviral therapy (HAART) regimen, stratified by protease inhibitor compared with no protease inhibitor regimens. Interval history was assessed, and lipid and lactate levels were drawn every 8 weeks during pregnancy and 12 weeks postpartum, with levels closest to delivery and postpartum used for analysis. Statistical comparisons used Kruskal-Wallis and Fisher exact tests. RESULTS: One-hundred fifty-eight women were evaluated. Total cholesterol levels (median 230 mg/dL, interquartile range [197, 259], compared with 212 [179, 246] mg/dL, P=.042) and triglycerides (median 224 mg/dL, interquartile range [187, 288], compared with 185 [142, 230] mg/dL, P<.001] were elevated in the protease inhibitor group during pregnancy and remained higher in this group after delivery (total cholesterol 185 [163, 224] mg/dl compared with 171 [140, 190] mg/dL, P<.004; triglycerides 122 [87, 175] mg/dL compared with 89 [66, 150] mg/dL, P=.02). No difference was seen in lactate levels or rates of gastrointestinal symptoms between groups. Obstetric outcomes were similar between the two groups. A higher number of low birth weight infants were born to women in the highest twentieth percentile of triglycerides compared with the lowest across medication groups. CONCLUSION: Cholesterol and triglycerides were higher in protease inhibitor-treated women in pregnancy. Lactate and gastrointestinal symptoms were not different. A higher number of low birth weight infants were noted in women with high triglycerides, but other elevated lipid levels did not affect pregnancy outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00017797 LEVEL OF EVIDENCE: II.