Objective: While treatment regimens combining two or three antiretrovirals have become standard for HIV-infected adults, concerns over perinatal safety have limited the widespread use of agents other than zidovudine (AZT) in pregnant women. While it has been suggested that maternal or neonatal side effects with newer nucleoside agents may not be significantly different from those reported in large-scale trials with AZT alone during pregnancy, no objective data from human pregnancies are available. We present our preliminary data from a policy offering AZT to all pregnant women, with the intent of decreasing vertical transmission in accordance with established guidelines, but that also offers a second nucleoside agent for maternal therapy, in accordance with current adult HIV protocols. Study Design: Beginning in 1996, HIV-infected women at our institution received extensive individual counseling and were offered therapy with both AZT and a second nucleoside if they were either AZT-non-naive or had abnormal lymphocyte subset profiles at diagnosis. Hematologic, chemistry, and lymphocyte profiles were followed through their pregnancies, with blood counts and liver function testing performed on all newborns. Results: From May 1996 to the present, nine women treated with double-nucleoside therapy have delivered; another two pregnancies are ongoing. AZT therapy (200 mg TID) was instituted or continued in women according to current guidelines at a median gestational age (GA) of 14 weeks (range 7-25), with two women already on therapy when pregnancy was diagnosed. A second nucleoside agent was prescribed in this cohort at a median GA of 24 weeks (range 14-37): two women early in the study period received didanosine (ddI), 250 mg BID; the others were treated with lamivudine (3TC), 150 mg BID. No patients stopped therapy for side effects and none had significant changes in hematologic or liverfunction values from baseline to delivery. All patients delivered at term (mean GA 38.7 ยฑ 1.1 wks), with a mean birthweight of 3182 ยฑ 620 gms. In the newborns, 4/9 had mild anemia (HCT<50%), with a mean Hgb of 14.3 ยฑ 4.7 gm/dl and Hct of 46 ยฑ 8.8%; their mean white blood cell and platelet counts were normal. No newborns required blood transfusions, and all were discharged with their mothers after normal exams in the nursery. Elevated transminases were seen in 7/9 newborns (mean SGOT 56 ยฑ 16 IU/l, SGPT 19 ยฑ 9 IU/l), but none required therapy for hyperbilirubinemia. Conclusions: Our experience with double-nucleoside therapy in this limited cohort of HIV-infected women provides early, objective support to its use during pregnancy for maternal indications. Effects on maternal and neonatal clinical status and lab profiles were comparable to those reported with AZT alone, and overall acceptance and tolerance were high.