The surface-active drugs chlorpromazine (CPZ) and imipramine (IP) have been tested on large unilamellar vesicles composed of phosphatidylcholine (PC), sphingomyelin (SM), and cholesterol (Ch) in different proportions. The well-characterized nonionic detergent Triton X-100 (TX) has also been used in parallel experiments. Leakage of vesicular aqueous contents and bilayer solubilization have been measured for each surfactant molecule and vesicle composition. All three surface-active molecules behave in a qualitatively similar way, irrespective of bilayer composition: they induce leakage at concentrations well below their critical micellar concentrations (cmc) and solubilization near the cmc. In these events, the potency of the three surfactants under study increases with decreasing cmc, in the order IP < CPZ < TX. With all three surfactant molecules, addition of SM to PC bilayers made the vesicles more sensitive to the detergents. The three surfactants had the same effects on PC: SM (3: 1 mole ratio) and on PC: SM: Ch(3: 1: 1 mole ratio) vesicles when leakage was tested. However, the presence of cholesterol made the bilayers more resistant to solubilization. In the presence of both SM and Ch, CPZ and IP, but not TX, were able to achieve complete bilayer solubilization. Since the outer monolayer of plasma membranes is rich in SM and Ch, the present data could be relevant in understanding some of the CPZ or IP effects at the membrane level.