Previous studies demonstrated that serum from cystic fibrosis (CF) patients specifically inhibited Pseudomonas phagocytosis by both normal and CF alveolar macrophages. In the present study, inhibition of Pseudomonas aeruginosa phagocytosis by CF serum was significantly less on macrophages from heavy smokers than on cells from normal volunteers (P less than 0.01). Normal volunteer cells cultured for 10 days were also less affected by CF serum as compared to cells cultured for 24 hours from the same individual (P less than 0.01). Altered morphology (increased size and spreading on glass surfaces) and increased intracellular glycosidases of these cells were suggestive of a difference in the state of activation compared to normal cells. Macrophages from heavy smokers and 10-day cultures from normal volunteers were inhibited by heated CF serum, suggesting that complement-mediated opsonization was responsible for attachment or ingestion of P. aeruginosa in CF serum by these macrophages.