The earliest structural change in hypoxia-induced pulmonary hypertension is increased proliferation of adventitial fibroblasts. This fibroproliferative response occurs in acute and chronic hypoxic models, is dependant on p38 mitogen-activated protein (MAP) kinase activation, is selective for the pulmonary circulation and would seem an important therapeutic target. Simvastatin attenuates pulmonary vascular remodeling in animal models but additional information regarding mechanisms of action, differential antiproliferative effects and dose responses of available statins is required for appropriate clinical trial design. To determine the effects of statins on acute hypoxia-induced proliferation and p38 MAP kinase activation in pulmonary and systemic artery fibroblasts, and assess the effects of cholesterol intermediates, prenyltransferase and related inhibitors, to determine the statin's mechanism of action. Atorvastatin, fluvastatin and simvastatin inhibited adventitial fibroblast proliferation. At low dose (1µM), this effect was selective for hypoxic (vs serum-induced) proliferation and was also selective for pulmonary (vs systemic) fibroblasts. Complete inhibition of hypoxia-induced p38 MAP kinase activity was achieved at this 1µM dose. The lipophilic statins exhibited similar potency. The statin effect was reversed by geranylgeranyl pyrophosphate and mimicked by geranylgeranyl transferase and Rac1 inhibitors. Hypoxia-induced p38 MAP kinase activation and proliferation in pulmonary adventitial fibroblasts is dependant on a geranylgeranylated signaling protein, probably Rac1. 1µM fluvastatin exhibits a circulation and stimulus selective antiproliferative effect on pulmonary artery fibroblasts. The pharmacokinetics of fluvastatin would suggest that its antiproliferative effects may be useful in pulmonary hypertension associated with hypoxia.