Some recent observations have indicated that cells other than mast cells, notably macrophages, may contain significant amounts of histamine. Using a histamine-specific radioimmunoassay, we found that human blood monocytes and lymphocytes contain about 0.05 pg histamine/cell. Various other cells, e.g. fibroblasts, colorectal tumor, kidney and ovarian cells, and murine bone marrow derived macrophages contained markedly less histamine (< 0.008 pg/cell). Ionophore A23187 (1 microM) released up to 50% of the total histamine from monocytes and lymphocytes. C5a caused a dose-dependent histamine release of up to 40% in monocytes and up to 20% in lymphocytes. Substance P induced a release only in cells of certain donors. Lipopolysaccharide, concanavalin A, and compound 48/80 had no effect. Culturing of the cells caused a loss of cellular histamine and its releasability. In view of the huge numbers of monocytes and lymphocytes in the blood, the histamine in these cells has to be taken into account under both physiological and pathophysiological conditions.