1. The opiate antagonist naloxone induces a positive inotropic effect in isolated cardiac muscles. 2. The response to naloxone is dependent on the presence of Na+ in the bathing solution, is proportional to the rate of electrical stimulation, and increased in the presence of veratridine. 3. Lowering [K+]o to 50% augments the response, while complete removal of K+ from the extracellular solution attenuates the response to naloxone. 4. Maximal concentration of naloxone decreases the inotropic effect of the cardiac glycoside ouabain. 5. The results indicate the involvement of intracellular sodium accumulation in the positive inotropic effect of naloxone, probably through the inhibition of the sarcolemmal Na(+)-K+ pump.