Human immunodeficiency virus (HIV)-associated pulmonary arterial hypertension (PAH) is a devastating, noninfectious complication of acquired immune deficiency syndrome, and the majority of HIV-PAH cases occur in individuals with a history of intravenous drug use (IVDU). However, although HIV-1 and IVDU have been associated with PAH independently or in combination, the pathogenesis of the disproportionate presence of HIV-PAH in association with IVDU has yet to be characterized. The objective of this study was to obtain a better understanding of the interactions between HIV-1 and cocaine to help uncover the mechanism(s) of the development of HIV-PAH. We observed that exposure of HIV-infected macrophages or HIV-Trans-Activator of Transcription (Tat)-treated pulmonary endothelial cells to cocaine enhanced the expression of platelet-derived growth factor (PDGF)-BB. Simultaneous treatment with Tat and cocaine, on the other hand, exacerbated both the disruption of tight junction proteins (TJPs), with enhanced permeability in pulmonary endothelial cells, and the proliferation of pulmonary smooth muscle cells (pSMCs) compared with either treatment alone. Histological examination of HIV plus IVDU human lung sections showed signs of early pulmonary arteriopathy, severe down-modulation of TJPs, and increased expression of PDGF-BB compared with the lung sections from individuals who are infected with HIV and without history of IVDU. Interestingly, blocking of PDGF receptor signaling with the receptor antagonist or small interfering RNA has been shown to inhibit the increase in proliferation of pSMCs on Tat and cocaine exposure. Our results, therefore, support an additive effect of cocaine to HIV infection in the development of pulmonary arteriopathy through enhancement of endothelial dysfunction and proliferation of pSMCs, while also suggesting PDGF-PDGF receptor axis as a potential target for use in clinical intervention.