In the dog heart-lung preparation the effects of glucose and mannitol induced hyperosmolality were examined on left ventricular water content, ventricular compliance, cardiac performance, and coronary blood flow. Glucose-induced increase of serum osmolality by more than 20% resulted in a decrease of myocardial water content and an increase of left ventricular diastolic stiffness if insulin was absent, but the changes did not develop if it was present. Insulin failed to prevent the alterations if hyperosmolality was induced with the nonmetabolizable sugar, mannitol. Coronary blood flow increased in each type of experiments. It is concluded that diagnostic and clinical treatment with hyperosmotic solutions of nonmetabolizable agents can account for disturbed left ventricular compliance and decreased cardiac performance, as it may occur in hyperosmolar diabetic coma.