The interactions of purified staphylococcal delta-lysin and melittin with various phospholipid monolayers containing different polar head groups and fatty acid moieties and with monolayers of cod and sheep erythrocyte lipids at various initial film pressures (pi i) were studied by using the Wilhelmy plate method. In each case the final increase in surface pressure (delta pi) was a linear function of pi i. In the case of delta-lysin, the critical pressures (pi c, the extrapolated values of pi i at delta pi = 0) for phosphatidylcholines with different fatty acid chain length, dipalmitoylphospholipids with different polar head groups, and cod or sheep erythrocyte total lipids fell within a relatively narrow range whereas melittin showed a much wider range. The collapse pressures of the delta-lysin and melittin films at the air-water interface when adsorbed from the hypophase were very similar. delta-Lysin showed little or no specificity in its interactions with all types of lipid films studied, whereas melittin showed preferential interaction with films of acidic lipid, similar to the specificity reported for cardiotoxins of Naja mossambica mossambica described by other workers.