Both guinea pig peritoneal exudate and human peripheral blood eosinophils produce large amounts of superoxide anion when stimulated by preopsonized zymosan or phorbol myristate acetate (PMA). Superoxide production is also activated by histamine but not the histamine metabolite, imidazole acetic acid. Supernatants from degranulated rat mast cells stimulate superoxide production. In studies of both human and guinea pig eosinophils, the H1-antagonist, chlorpheniramine (10-3 M and 10-4 M), preopsonized zymosan histamine) production of superoxide anion but the H2-antagonist, cimetidine, only modestly inhibited superoxide anion production (zymosan, PMA), These studies provide direct evidence for the influence of histamine on the oxidative metabolism of eosinophils. These results are consistent with the hypothesis that histamine interacts with eosinophils predominantly via an H1 receptor site. Furthermore, they suggest that eosinophils may participate in immediate hypersensitivity reactions by the release of superoxide anion in response to stimulation by histamine.