Human stomach adenocarcinoma (AGS), astrocytoma (AST) and myelogenous leukemia (K562) cells were co-cultured with human peripheral blood leukocytes (PBL) through four days. Histamine releasing activity (HRA, lymphokines that stimulate degranulation of basophilic leukocytes with the release of histamine) and interferons alpha and gamma (IFN alpha and IFN gamma) were detected in the culture fluids. Maximal levels of HRA were detected by 24 hr in AST and K562-leukocyte co-culture fluids. Notably, only low levels of HRA was detected in AGS-leukocyte cultures. HRA was separated into two molecular weight species (60,000 and 25,000) by column chromatography. The IFN activity was shown to be a mixture of IFN alpha and IFN gamma (IFN alpha greater than IFN gamma). IFN did not cause histamine release from human PBL or affect HRA. Our results indicate that PBL from normal individuals produce HRA in response to tumor antigen and suggest that the basophilic leukocyte response to certain cancers may be related to HRA production.