Rationale: Fluoxetine is a selective serotonin reuptake inhibitor antidepressant widely used by pregnant women. Recent epidemiological data suggest that fluoxetine exposure prenatally increases the prevalence of the persistent pulmonary hypertension syndrome of the newborn. The mechanism responsible for this effect is unclear and paradoxical to the current evidence of a pulmonary hypertension protective fluoxetine effect in adult rodents. Objectives: To evaluate the fluoxetine effect on the fetal rat pulmonary vascular smooth muscle mechanical properties and cell proliferation rate. Methods and Measurements: Pregnant rats were treated with fluoxetine (10 mg/kg) from the 11^th through 21 days of gestation. Results: The fetuses were delivered by Cesarean section. As compared with controls, fluoxetine exposure resulted in fetal pulmonary hypertension as evidenced by an increase in the right-to-left ventricle+septum ratio (P=0.02) and pulmonary arterial medial thickness (P<0.01). Postnatally the mortality was increased in the experimental animals and the arterial oxygen saturation was 96±1% in the one day old control animals and significantly lower (P<0.01) in the fluoxetine-exposed pups (79±2 %). In vitro, fluoxetine induced pulmonary arterial muscle contraction in the fetal, but not adult (P<0.01) and reduced at both ages (P<0.01) the serotonin-induced contraction. Following in utero exposure to a low fluoxetine concentration the pulmonary arterial smooth muscle cell proliferation rate was significantly increased in fetal, but not adult cells (P<0.01). Conclusions: In contrast to the adult, fluoxetine exposure in utero induces pulmonary hypertension in the fetal rat as a result of a 2 developmentally regulated increase in pulmonary vascular smooth muscle proliferation.