Phospholipidosis, the accumulation of phospholipids in cells, is a relatively frequent side effect of cationic amphiphilic drugs. In response to the industry need, several methods have been recently published for the prediction of the phospholipidosis-inducing potential of drug candidates. We describe here a high-throughput physicochemical approach, which is based on the measurement of drug-phospholipid complex formation observed by their effect on the critical micelle concentration (CMC) of a short-chain acidic phospholipid. The relative change due to the drug, CMC(DL)/CMC(L) provides a direct measure of the energy of the drug-phospholipid association, irrespective of the nature of the interaction. Comparison of results for 53 drugs to human data, animal testing, cell culture assays, and other screening methods reveals very good correlation to their phospholipidosis-inducing potential. The method is well suited for screening already in early phases of drug discovery.