Human alveolar macrophages (AMs) and blood monocytes were obtained from 65 smoking and nonsmoking normal volunteers and 29 patients with lung cancer. The oxidative metabolic response of these cells was measured by superoxide anion production after incubation with lipopolysaccharide. In addition, tumoricidal activity of AMs and monocytes was assessed against [3H]thymidine-labeled tumor target cells. Smoking was associated with depressed AM superoxide anion responses in normals but not in patients. In contrast, smoking appeared to slightly elevate monocyte superoxide anion activity. AMs and monocytes exposed to lipopolysaccharide or recombinant gamma-interferon showed tumoricidal activity in all groups. Mean cytotoxicity values of smoking patients versus smoking normals and exsmoking patients versus nonsmoking normals were not significantly different. Smoking, however, in both patients and normals was associated with significantly (P less than 0.005) depressed AM cytotoxicity levels (less than 40%) compared to nonsmoking volunteers and exsmoking patients. Activated AMs from cancer patients and normals were cytotoxic against three different tumorigenic cell lines but not against a nontumorigenic line. No correlation between monocyte and AM cytotoxic activity within single individuals was found. We conclude that AM and monocytes from smoking and exsmoking patients can be activated after exposure to immunomodulators; however, smoking may be slightly suppressive to cytotoxic responses. These studies provide a rationale for clinical trials of immunomodulators in patients with lung cancer.