Histamine inhibits superoxide anion (O-2) production from human neutrophils stimulated by N-formylmethionyl-leucyl-phenylalanine (FMLP). The effects of histamine are dose-dependent and competitively antagonized by cimetidine. When passively sensitized rat serosal mast cells and human neutrophils are mixed together, O-2 production from FMLP-activated granulocytes is significantly reduced, following mast cell degranulation by acetylcholine. These inhibitory effects can be counteracted by cimetidine. Exposure of non-sensitized rat mast cells to FMLP-stimulated human neutrophils causes histamine release. These results suggest bidirectional control mechanisms between mast cells and neutrophils, that further stress the role of histamine in regulating inflammatory processes.