Addition of ouabain caused gradual increases of both the Na content of cultured myocardial cells and the rate of Ca++ uptake by the cells. Ouabain-induced irregular beating of the cells (ouabain toxicity) appeared to develop when the Na content and the rate of Ca++ uptake exceeded about 1.5 and 2.0 times, respectively, the normal levels. Quinidine and procainamide prevented ouabain-induced increases of the Na content and the rate of Ca++ uptake as well as ouabain-induced toxicity. The problem of how quinidine and procainamide counteract the effects of ouabain was then studied. Quinidine and procainamide did not affect the Na+-Ca++ exchange activity. Na+,K+-adenosine triphosphatase activity, Na+-pumping out activity or ouabain-binding activity of myocardial cells, but inhibited passive Na+ influx, which is achieved by a simple diffusion system. From these observations, it is suggested that inhibition by quinidine or procainamide of passive Na+ influx indirectly prevents ouabain-induced increase in the intracellular Na content of myocardial cells and that this presumably explains at least in part the inhibitory effect of quinidine and procainamide on ouabain-induced irregular beating.