A single intraperitoneal injection of Compound 48/80 in rats causes mast cell activation which is followed by a proliferation in fibroblasts and mesothelial cells in the mesentery. The same is true of organ‐cultured rat mesentery, but in cultured guinea‐pig mesentery Compound 48/80 has no morphological effects on mast cells and does not induce proliferation. The relationship between mast‐cell secretion and cell proliferation in surrounding cells was studied further in the investigation now presented. Proliferation was estimated (a) by cytophotometric Feulgen DNA measurements in individual fibroblast and mesothelial cell nuclei; (b) by measurements of incorporation of3H‐TdR into DNA; (c) and by estimation of mitotic frequency. Mast‐cell secretion was studied morphologically and by biochemical quantitation of histamine release. Compound 48/80 is a potent mast cell activator in the rat, stimulating mast cells to secretion. The results of this study suggest that Polymyxin B, another powerful mast‐cell activator, apparently chemically unrelated to Compound 48/80, also stimulates the mesenterial cells to proliferation in the rat. In the guinea‐pig Compound 48/80 does not induce mast‐cell secretion or proliferetion in fibroblasts and mesothelial cells in the mesentery. The results give further evidence that the cell proliferation induced by Compound 48/80 and Polymyxin B in rat mesentery is causally related to mast