Rationale: Epidermal growth factor (EGF) and its receptors play a role in cell proliferation and survival and are implicated in the pathobiology of pulmonary arterial hypertension (PAH). Objective and methods: We investigated a) the effects of three clinically approved EGF receptor (EGFR) antagonists in vitro on rat pulmonary arterial smooth muscle cell (PASMC) proliferation and in vivo on experimental pulmonary hypertension (PH) induced by monocrotaline injection in rats and by chronic hypoxia in mice, and b) the expression of EGFR in the lung tissues from experimental and clinical PH. Measurements and main results: The EGFR inhibitors, gefitinib, erlotinib and lapatinib inhibited the EGF-induced proliferation of PASMCs. In rats with established PH, gefitinib and erlotinib significantly reduced right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). In addition, the medial wall thickness and muscularization of pulmonary arteries were improved. In contrast, lapatinib did not provide therapeutic benefit. These EGFR antagonists at their highest tolerable dose did not yield significant improvement in RVSP, RVH and pulmonary vascular remodeling in mice with chronic hypoxic PH. Moreover, no significant alteration in the EGFR expression was detected in the lung tissues from patients with idiopathic PAH (IPAH). Conclusion: The partial therapeutic efficacy of the EGFR antagonists in animal models of pulmonary hypertension and the absence of significant alteration in EGFR expression in the lungs from IPAH patients suggest that the EGFR do not represent a promising target for the treatment of pulmonary hypertension.