The emerging condition of HIV-related pulmonary hypertension produces histologic manifestations closely mimicking those seen in primary pulmonary hypertension, including abnormalities in the endothelial and smooth muscle cells, medial hypertrophy, concentric intimal proliferation, and nearly complete luminal obstruction. Macaques infected with recombinant chimeric simian immunodeficiency virus (SIV)/HIV (SHIV) constructs in which one or more SIV gene products are replaced with those from HIV represent a model of HIV immunodeficiency in which components of the human virus may be assessed for their potential contributions to pathologic conditions. We surveyed 24 animals from three different cohorts that were infected with various SIV and SHIV constructs, four of which were an SHIV recombinant virus containing the HIV nef gene. We observed examples of arteriopathy including medial hypertrophy, perivascular cuffing by inflammatory cells, thrombosis, and pulmonary vascular lesions with recanalized lumens exclusively in tissues from the SHIV nef animals. The characterization of these lesions with endothelial and smooth muscle-specific markers by immunohistochemistry revealed that the endothelial cell core of the lesion often stained intensely for platelet-endothelial cell adhesion molecule-l (CD31) and von Willebrand factor (factor VIII), and the thickened media stained with a muscle-specific actin. We propose that the SHIV nef-infected macaque provides a novel primate model to explore the development and natural progression of HIV-related pulmonary hypertension and primary pulmonary hypertension.