Virus-induced exacerbations often lead to further impairment of lung function in chronic obstructive pulmonary disease. IL-15 is critical in antiviral immune responses. Retinoic acid (RA) signaling plays an important role in tissue maintenance and repair, particularly in the lung. We studied RA signaling and its relation to IL-15 in the lung during cigarette smoke (CS) exposure and influenza virus infection. In vivo studies show that RA signaling is diminished by long-term CS exposure or influenza virus infection alone, which is further attenuated during infection after CS exposure. RA receptor beta (RAR beta) is specifically decreased in the lung of IL-15 transgenic (overexpression; IL-15Tg) mice, and a greater reduction in RAR beta is found in these mice compared with wild-type (WT) mice after infection. RAR beta is increased in IL-15 knockout (IL-15KO) mice compared withWTmice after infection, and the additive effect of CS and virus on RARb down-regulation is diminished in IL-15KO mice. IL-15 receptor a (IL-15Ra) is increased and RAR beta is significantly decreased in lung interstitial macrophages from IL-15Tg mice compared with WT mice. In vitro studies show that IL-15 downregulates RAR beta in macrophages via IL-15Ra signaling during influenza virus infection. These studies suggest that RA signaling is significantly diminished in the lung by CS exposure and influenza virus infection. IL-15 specifically down-regulates RAR beta expression, and RAR beta may play a protective role in lung injury caused by CS exposure and viral infections.