Upon incubation of the anticancer drug cisplatin [cis-diamminedichloroplatinum(II)] with model membranes composed of phosphatidylserine (PS), a stable product is formed that has been isolated after chloroform/methanol extraction of the sample. The product formation is specific for PS and does not occur with other major membrane phospholipids. The rate and extent of product formation is dependent on the pH, chloride ion concentration, and temperature, with the highest rate at pH 6.0, in the absence of Cl- and at 37 degrees C, indicating that positively charged aquated cisplatin is the reactive species. Over 80% of PS is converted within 15 h under these conditions with a halftime of 5 h. PS can be regenerated by an excess of glutathione. Mass spectrometry experiments demonstrate that interaction of cisplatin with PS involves a loss of two chloride ions and coordination of platinum to the amine and carboxyl group of the serine moiety. Cisplatin forms complexes specifically with PS not only in model membranes but also in the plasma membrane of human erythrocytes. Since PS is essential in several cellular processes, its interaction with cisplatin may have important physiological implications.