Chronic Obstructive Pulmonary Disease (COPD) is a syndrome that comprises several distinct and overlapping phenotypes. In addition to persistent airflow limitation and respiratory symptoms, COPD is also characterized by chronic systemic inflammation. Epidemiological studies have shown that dietary fibers, fruits and vegetables intake protects against the COPD development, while fructose-loading is associated with increased risk of asthma and chronic bronchitis. Since dietary factors might affect susceptibility to COPD by modulating oxidative stress and inflammatory responses, we evaluated how fructose feeding might affect the smoking-induced emphysema in mice. We found that chronic fructose intake induced destruction and remodeling of lung parenchyma and impairment of respiratory mechanics, which are associated with distinctive cytokine profiles in bronchoalveolar lavage fluid, blood plasma and skeletal muscle. The combined effects of chronic fructose intake and cigarette smoking on destruction of lung parenchyma are more pronounced than the effects of either alone. Excessive intake of fructose might directly cause pulmonary emphysema in mice rather than just altering its natural history by facilitating the installation of a low-grade systemic inflammatory milieu.