On chronic treatment certain amphiphilic drugs induce a generalized phospholipidosis. This drug side effect has been related to an inhibition of the lysosomal phospholipases due to the interaction of the drugs with phospholipids (PL). In the present experiments, the influence of the amphiphilic drugs ambroxol, imipramine, chloroquine and chlorphentermine on the hydrolysis of dipalmitoyl-phosphatidylcholine (DPPC) unilamellar liposomes by bee venom phospholipase A2 (PLase A2) was studied. Special emphasis was laid on the initial phase and temperature dependence. The activity of PLase A2 was measured continuously with a spectrophotometric assay using cresol red as indicator. In most cases a lag-phase of different duration was observed before the enzyme exhibited its full activity. The duration of the lag-phase and the rate of hydrolysis in the second phase are inversely related. The temperature dependence of the hydrolysis reveals a maximum of activity near the phase transition of the bilayer and a gradually decreasing activity at lower and higher temperatures, respectively. The analysis of the influence of amphiphilic drugs reveals three types of interaction. Imipramine and ambroxol shift the temperature activity profile towards lower temperatures without a substantial influence on the shape of the profile and on the maximal rate of hydrolysis. Chloroquine inhibits the enzyme activity without any temperature dependence. Chlorphentermine, the classical lipidosis inducing drug, exhibits a third type of interaction which seems to be a combination of the two former types.