Whole killed cells, cell walls, and peptidoglycans of Staphylococcus aureus were found to release histamine from human leukocytes and isolated rat mast cells in vitro. The histamine-releasing capability increased in the order of whole bacteria, cell walls, and peptidoglycans. Peptidoglycan was found to release histamine by a nonimmunological mechanism, as demonstrated by release in cells deprived of surface immunoglobulins, whereas whole bacteria and cell walls seemed to operate both by immunological and nonimmunological mechanisms. Histamine release was not a specific property of S. aureus; a wide range of whole bacterial species had this activity. We suggest that peptidoglycan may be a common factor responsible for histamine release by different bacteria.