The mechanism of histamine release from rat mast cells by whole venom from Solenopsis geminata and S. invicta or by 2-methyl-6-undecylpiperidine HCl (C11) was investigated. Histamine release stimulated by one or more of these agents (1) occurred in normal and metabolically inactivated cells, (2) had a biphasic time course in normal and inactivated cells, (3) was temperature dependent and did not occur at 0 degrees C, (4) was accompanied by concomitant cytoplasmic enzyme release, (5) was accomplished by substantial cell swelling, and (6) was correlated with a loss of cell refractility in phase contrast microscopy. These results indicate that C11 causes initial permeability changes in the plasma membrane followed by lytic release of histamine and other cell components. The nonspecific nature of this action of the dialkylpiperidine component of the venoms provides the fire ants with a defense of general applicability.