Objective: In isolated myocytes cardioplegia-induced cell swelling can be prevented by lowering the KCI product by replacing Cl- with an impermeant ion. This study tested the hypothesis that Cl- substitution in St. Thomas' Hospital cardioplegic solution would result in superior myocardial protection in the intact, blood-perfused heart. Methods: Using a parabiotic, isolated rabbit heart Langendorff model, hearts were exposed to 1 hour of hypothermic (10°to 12°C), global ischemia followed by 30 minutes of reperfusion. Isosmotic cardioplegia was administered as a single 50 ml bolus of either standard St. Thomas' Hospital solution ([K+](o) x [Cl-](o) = 2566.4 (mmol/L)2) or low Cl- St. Thomas' Hospital solution ([K+](o) x [Cl-](o) = 700 (mmol/L)2). Chloride was replaced by a large, impermeant ion, methanesulfonate. Postreperfusion systolic function and atrioventricular conduction times were measured before ischemia and after reperfusion. Results: Hearts receiving low Cl- St. Thomas' Hospital cardioplegia demonstrated significantly better postischemic functional recovery (74% ± 3%) compared with those treated with standard high Cl- St. Thomas' Hospital solution (55% ± 4%, p = 0.003). In addition, atrioventricular conduction times remained normal in the low Cl- group but were significantly prolonged in the St. Thomas' Hospital group. Conclusions: Lowering the KCl product of St. Thomas' Hospital solution makes it isotonic with plasma and prevents cellular edema. This ameliorates the detrimental functional and electrophysiologic sequelae of hypothermic, hyperkalemic cardioplegia.