Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death worldwide. We report in an emphysema model of mice chronically exposed to tobacco smoke that pulmonary vascular dysfunction, vascular remodeling, and pulmonary hypertension (PH) precede development of alveolar destruction. We provide evidence for a causative role of inducible nitric oxide synthase (iNOS) and peroxynitrite in this context. Mice lacking iNOS were protected against emphysema and PH. Treatment of wild-type mice with the iNOS inhibitor N6-(1-iminoethyl)-L-lysine (L-NIL) prevented structural and functional alterations of both the lung vasculature and alveoli and also reversed established disease. In chimeric mice lacking iNOS in bone marrow (BM)-derived cells, PH was dependent on iNOS from BM-derived cells, whereas emphysema development was dependent on iNOS from non-BM-derived cells. Similar regulatory and structural alterations as seen in mouse lungs were found in lung tissue from humans with end-stage COPD. Display omitted ► Inducible nitric oxide synthase (iNOS) loss protects mice from smoke-induced emphysema ► Pulmonary hypertension is dependent on iNOS activity in bone marrow-derived cells ► Emphysema is dependent on iNOS activity in non-BM-derived cells ► The iNOS inhibitor L-N6-(1-iminoethyl)-lysine improves established emphysema in mice Smoking-related damage can be reversed by inhibition of iNOS.