Abstract Starting from the discovery of Saks et al. (Saks, V.A., Lipina, N.V., Sharov, V.G., Smirnov, V.N., Chazov, E.I. and Grosse, R. (1977) Biochim. Biophys. Acta 465, 550–558) that the kinetic coupling of (Na + + K +)-ATPase and creatine phosphokinase, both residing in the plasma membrane of cardiac muscle cell, renders possible the effective utilization of phosphocreatine for the phosphorylation of ADP produced in (Na + + K +)-ATPase turnover, the present paper investigates and evidences the faculty of the coordinate interplay between (Na + + K +)-ATPase and creatine phosphokinase to optimize the (Na +/K +)-antiport across the membrane of vesicles formed from the plasma membrane of cardiac muscle cell. 1. (1) The plasma membrane preparation used consists of 13% right-side-out vesicles and 87% inside-out vesicles of which the latter exhibit the catalytic centres of (Na + + K +)-ATPase and associated creatine phosphokinase on the extravesicular face. The V values of the two enzymes are similar so that they may show a coordinate interplay under substrate-saturating conditions. 2. (2) The vesicles are impermeable to ATP and phosphocreatine, but show a relatively high permeability to Na + and K + so that an inward uphill transport of Na + and an outward uphill transport of K + can only be traced when their rates exceed the rates of the passive back diffusions of the cations through the vesicle membrane.