OBJECTIVE: To analyze the influence of highly active antiretroviral treatment (HAART) on risk factors for perinatal transmission of human immunodeficiency virus (HIV). DESIGN: A prospective cohort study was performed between HIV pregnant women under HAART therapy and without treatment. SETTING: The maternity hospital 'La Fe' in Valencia, Spain. POPULATION OR SAMPLE: Five hundred HIV-positive pregnant women. METHOD: Known maternal and obstetrical perinatal risk factors were analyzed by univariate and multivariate methods (logistic regression). The influence of HAART on the risk factors was evaluated independently to determine whether there was a modulation in perinatal HIV transmission. MAIN OUTCOME MEASURES: Known perinatal risk factors were found not to have any significant influence on perinatal HIV transmission in women under HAART therapy. RESULTS: Vertical transmission risk decreased significantly from 18.2% without treatment to 8.6% with mono/dual therapy and 0.6% with HAART. A CD4+ cell count below 500 cell/microl, intrapartum use of invasive procedures, rupture of membranes >six hours, labor length >five hours, and birthweight were the significant risk factors associated to vertical HIV transmission and elective cesarean section. Antiretroviral treatment administered during delivery was a protective factor in HIV pregnant women before HAART therapy. CONCLUSIONS: HAART therapy reduces the influence of the perinatal risk factors on vertical HIV transmission.