Unexplained weight loss is common in chronic obstructive pulmonary disease (COPD). Blood levels of tumor necrosis factor-alpha (TNF-alpha), a cytokine causing cachexia in laboratory animals, are elevated in various human diseases associated with weight loss. We therefore prospectively measured TNF-alpha serum levels (immunoradiometric assay) in patients with clinically stable COPD (n = 30; all male; mean age, 65 yr) whose weight was less (Group I; n = 16) or more (Group II; n = 14) than the lower limit of normal taken from Metropolitan Life Insurance Company tables. The patients had no cause known to elevate TNF-alpha serum levels; notably, they were not infected. Group I patients had unintentionally lost weight during the previous year, whereas the weight of Group II patients had not changed during the same period. The two groups had similar chronic airflow obstruction and arterial blood gas impairment; hyperinflation and reduction in diffusing capacity were more pronounced in Group I, but differences were not significant. TNF-alpha serum levels (pg/ml; mean [SD]) were significantly higher in Group I than in Group II (70.2 [100.0] versus 6.7 [6.4]; p < 0.001). Group II TNF-alpha serum levels did not differ significantly from those of healthy subjects (7.8 [3.9]), whereas those of Group I were significantly higher (p < 0.001). Because renal function was in the normal range, we conclude that increased TNF-alpha production--and not decreased TNF-alpha clearance--is a likely cause of weight loss in patients with COPD.