Cigarette smoke usage is prevalent in HIV+ patients and, despite highly active antiretroviral therapy (HAART), these individuals develop an accelerated form of chronic obstructive pulmonary disease (COPD). Studies investigating the mechanisms of COPD development in HIV have been limited by the lack of suitable mouse models. Here we describe a model of HIV induced COPD in wild type mice using EcoHIV, a chimeric HIV capable of establishing chronic infection in immunocompetent mice. A/J mice were infected with EcoHIV and subjected to whole body cigarette smoke exposure. EcoHIV was detected in alveolar macrophages of mice. Compared to uninfected mice, concomitant EcoHIV infection significantly reduced forced expiratory flow (FEF) 50%/forced vital capacity (FVC) and enhanced distal airspace enlargement following cigarette smoke exposure. Lung IL-6, G-CSF, neutrophil elastase, cathepsin G and MMP9 expression was significantly enhanced in smoke-exposed EcoHIV-infected mice. These changes coincided with enhanced IBα, ERK1/2, p-38 and STAT3 phosphorylation and lung cell apoptosis. Thus, the EcoHIV smoke exposure mouse model reproduces several of the pathophysiologic features of HIV-related COPD in humans, indicating that this murine model can be utilized to determine key parameters of HIV-related COPD and to test future therapies for this disorder.