Preeclampsia, a leading cause of maternal death and premature birth, is characterized by hypertension, compromised placental perfusion and intrauterine growth restriction. The complement system, part of the innate immune system, is activated in normal pregnancy with increased activation apparent in preeclampsia. We recently reported that inhibiting complement system activation with a soluble form of endogenous complement receptor significantly attenuated reduced uterine perfusion pressure (RUPP)-induced hypertension in the pregnant rat without affecting fetal resorptions or decreased circulating vascular endothelial growth factor. Since the vasoactive complement activation product C3a increased in serum following placental ischemia, we hypothesized that C3a is an important mediator of placental ischemia-induced hypertension. Using the RUPP model of hypertension in preeclampsia, we determined the effect of the C3a receptor antagonist SB290157 (N2-[(2,2-Diphenylethoxy)acetyl]-L-arginine) on changes in blood pressure and fetal weight following placental ischemia. On gestation day 14, clips were placed on abdominal aorta and uterine arteries to decrease placental perfusion. All dams received 5 mg/kg SB290157 or 10% ethanol/saline (Veh) iv on days 14-18. Mean arterial pressure (MAP) was measured on day 19 via arterial catheter and fetal weights were subsequently assessed. SB290157 treatment of rats that underwent sham surgery (Sham SB, n=6) did not affect either MAP or fetal weights compared to Sham Veh. MAP increased in RUPP Veh rats compared to Sham Veh (RUPP Veh, n=7, 109±2 mm Hg; Sham Veh, n=7, 94±2; p<0.05) and average fetal weights decreased (Sham Veh, 2.52±0.07 g; RUPP Veh, 2.24±0.07 g; p<0.05). Treatment of RUPP rats with SB290157 attenuated increased MAP (RUPP Veh, 109±2 mm Hg; RUPP SB, n=9, 101±2; p<0.05) but did not prevent decreased fetal weight (RUPP Veh, 2.24±0.07 g; RUPP SB, 2.20±0.07 g). These data suggest C3a is partly responsible for placental ischemia-induced hypertension and provide important new evidence to support a link between complement activation and hypertension. Inhibitors of complement activation or C3a antagonists may be viable new treatment strategies for managing new-onset hypertension in preeclampsia.