Caveolin-1, the structural and signaling protein of caveolae, is an important negative regulator of endothelial nitric oxide synthase (eNOS). We observed that mice lacking caveolin-1 (Cav1^-/-) had 2-fold increased plasma NO levels but developed pulmonary hypertension. We measured pulmonary vascular resistance (PVR) and assessed alterations in small pulmonary arteries to determine the basis of the hypertension. PVR was 46% greater in Cav1^-/- mice than wild-type (WT) and increased PVR in Cav1^-/- mice was attributed to pre-capillary sites. Treatment with L-NAME to inhibit NOS activity raised PVR by 42% in WT but 82% in Cav1^-/- mice, indicating greater NO-mediated pulmonary vasodilation in Cav1^-/- mice compared to WT. Pulmonary vasculature of Cav1^-/- mice was also less reactive to the vasoconstrictor thromboxane A2 mimetic (U46619) compared to WT. We observed redistribution of type I collagen and expression of smooth muscle -actin in lung parenchyma of Cav1^-/- mice compared to WT suggestive vascular re-modeling. Fluorescent agarose casting also showed markedly decreased density of pulmonary arteries and artery filling defects in Cav1^-/- mice. Scanning electron microscopy of showed severely distorted and tortuous pulmonary pre-capillary vessels. Thus, caveolin-1 null mice have elevated PVR that is attributed to remodeling of pulmonary pre-capillary vessels. The elevated basal plasma NO level in Cav1^-/- mice compensates partly for the vascular structural abnormalities by promoting pulmonary vasodilation.