Chronic obstructive pulmonary disease (COPD) is frequently associated with extrapulmonary complications, including cardiovascular disease, diabetes, and osteoporosis. Persistent, low-grade, systemic inflammation underlies these comorbid disorders. Tetraspanins, which have a characteristic structure spanning the membrane four times, facilitate lateral organization of molecular complexes and thereby form tetraspanin-enriched microdomains that are distinct from lipid rafts. Recent basic research has suggested a preventive role of tetraspanin CD9 in COPD. CD9-enriched microdomains negatively regulate LPS-induced receptor formation by preventing CD14 from accumulating into the rafts, and decreased CD9 in macrophages enhances inflammation in mice. Mice doubly deficient in CD9 and a related tetraspanin, CD81, show pulmonary emphysema, weight loss, and osteopenia, a phenotype akin to human COPD. A therapeutic approach to up-regulating CD9 in macrophages might improve the clinical course of patients with COPD with comorbidities.