In severe forms of human pulmonary hypertension (PH), both T-lymphocytes and B-lymphocytes have been found in complex pulmonary vascular lesions. However, whether or how the immune cells influence lung vascular remodeling has not been investigated. In rat models of pulmonary arterial hypertension, the degree of PH and pulmonary vascular remodeling depends on strain differences.1–4 To address the question whether functionally mature T-cells and a normal thymus play a role in the development of PH, we treated athymic nude rats (NIH-rnu) with the vascular endothelial growth factor receptor inhibitor SU-5416 at Denver altitude and in combination with chronic hypoxia. Athymic rats treated with SU-5416 at Denver altitude for 3 weeks acquired pronounced right ventricular (RV) hypertrophy (RV/LV + S = 0.5 ± 0.02 vs 0.25 ± 0.02 in untreated nude or SU-5416–treated Sprague-Dawley rats, where LV = left ventricle, and S = septum); they also acquired PH with a pulmonary artery pressure (PAP) of 47 ± 3.1 mm Hg and vascular lesions similar to those found in Sprague-Dawley rats treated with SU-5416 and chronic hypoxia. Athymic rats exposed for 3 weeks to hypoxia alone acquired PH with a PAP of 41 ± 2.5 mm Hg (compared to 35 ± 1.8 mm Hg in Sprague-Dawley rats) and a RV/LV + S = 0.5 ± 0.03 (vs 0.27 ± 0.02 in Sprague-Dawley rats). SU-5416–treated athymic rats exposed to hypoxia die within 3 weeks, whereas comparable Sprague-Dawley rats all survive with a PAP of 60 mm Hg and an RV/LV + S of 0.58 ± 0.02. Passive transfer of splenocytes from euthymic rats of the same genetic background protected athymic rats against SU-5416–induced PH at Denver altitude. In conclusion, athymic nude rats acquire more severe PH than euthymic rats. Our data suggest that functionally mature T-lymphocytes play a protective role in vascular remodeling and apparently contribute to the maintenance of the lung structures in situation of stress. The contribution of B-cells to the lung maintenance program remains to be investigated.