Increasing evidence suggests that neuropeptides may be important stimuli for mast cell secretion. Neuropeptide-induced histamine secretion from rat mast cells was inhibited by a variety of clinical and experimental antiallergic agents. The profile of responsiveness to this panel of drugs exhibited by peritoneal (PMC) and intestinal mucosal mast cells (IMC) was similar to that previously reported when histamine release was immunologically induced. Thus, cromoglycate, theophylline and Ro 22-3747 inhibited peptide-induced secretion from PMC but not from IMC. In contrast, doxantrazole was effective against PMC and IMC. Differences between IMC and PMC could not be attributed to the IMC isolation procedure. The results confirm the heterogeneity of responsiveness to antiallergic drugs exhibited by these mast cell subpopulations and indicate that it is not limited to immunologically induced secretion but also occurs when a neuropeptide is the secretory stimulus.