Patients with their first myocardial infarction not initially complicated by severe atrioventricular block or power failure were given a skin test and then randomized to receive either hyaluronidase or placebo in double-blind fashion. Hyaluronidase, 500 IU/kg i.v., was given every 6 hours for 42 hours. Of the 48 eligible patients, 26 received hyaluronidase and 22 received placebo. The mean CK serum entry was 3140 +/- 2111 mIU/ml (mean +/- SD) in hyaluronidase patients and 3574 +/- 1476 mIU/ml in placebo patients (p less than 0.21). The mean infarct size was 54.6 +/- 35.8 CK gram-equivalents in the hyaluronidase patients and 64.0 +/- 31.1 CK gram-equivalents in the placebo patients (p less than 0.20). Among the 21 patients treated within 6 hours of the onset of infarction, the difference in infarct size was greater (p less than 0.15). There was no significant difference in the incidence of power failure, ventricular arrhythmias, recurrence of ischemic pain, infarct extension or mortality. No benefit of hyaluronidase was demonstrated in this study, which was designed to detect a 50% reduction of infarct size. However, to detect a 20% reduction in infarct size would require a much larger study population.