Recurrent lung infections are a common cause of morbidity and mortality in people living with HIV and this is exacerbated in smokers even when administered combination antiretroviral therapy (cART). The incidence of pneumonia is increased with smoking and treatment interruption and is directly dependent on viral load in patients when adjusted for CD4 counts. CFTR dysfunction plays an important role in aberrant airway innate immunity as it is pivotal in regulating mucociliary clearance (MCC) rates and other antibacterial mechanisms of the airway. In our earlier work, we have demonstrated that bronchial epithelium expresses canonical HIV receptors CD4, CCR5 and CXCR4 and can be infected with HIV. HIV Tat suppresses CFTR mRNA and function via TGF-β signaling. In the present study, we demonstrate that cigarette smoke (CS) potentiates HIV infection of bronchial epithelial cells by upregulating CD4 and CCR5 expression. HIV and CS individually and additively suppress CFTR biogenesis and function, possibly explaining the increased incidence of lung infections in HIV patients and its exacerbation in HIV smokers.