Pulmonary hypertension remains an important cause of morbidity and mortality. Although there is currently no cure, descriptions of defective intracellular trafficking and protein misfolding in vascular cell models of pulmonary hypertension have been recently reported. We tested the hypothesis that activation of the unfolded protein response (UPR) would be associated with the development of severe PH. We investigated activation of the UPR in archival tissues from patients with severe PH, and in the monocrotaline-induced rat model of severe PH. We tested the ability of a pharmacologic agent capable of modulating the UPR to prevent and reverse pulmonary hypertension. We found evidence of an active UPR in archival tissue from humans with PH, but not in control lungs. Similarly, monocrotaline-treated rats demonstrated a significant difference in expression of each of the major arms of the UPR compared to controls. Interestingly, the UPR preceded the appearance of macrophages and the development of lung vascular remodeling in the rats. Treatment of monocrotaline rats with salubrinal, a modulator of the PERK arm of the UPR, attenuated PH and was associated with a decrease in lung macrophages. In culture, pulmonary artery smooth muscle cells with UPR induction produced IL-6 and CCL-2/MCP-1, and stimulated macrophage migration. These effects were abolished by pretreatment of cells with salubrinal. These data support the hypothesis that the UPR may play a role in the pathogenesis of inflammatory vascular remodeling and PH. As such, understanding the functional contributions of the UPR in the setting of PH may have important therapeutic implications.