The purpose of this study was to determine (1) if there is a relationship between the changes in the plasma levels of atrial natriuretic peptide (ANP) and plasma renin activity (PRA) as rats compensated from 3 days to 6 weeks after coronary ligation and (2) if these changes are related to myocardial infarction (MI) size. Arterial blood was drawn twice from 34 conscious rats (control, n = 10; small MI, n = 10; large MI, n = 14). Histologic MI size correlated better with ANP 3 days (r = .72, P < .001) than with ANP 6 weeks after MI (r = .39, P = .021). The reverse was true for an electrocardiographic index of MI size that used the sum of the Q waves minus the sum of the R waves in leads I, aVL, and V5. Atrial natriuretic peptide at 3 days was increased in both MI groups and was highest in the large MI group (control, 25.6; small MI, 41.0; large MI, 58.6 pM). Atrial natriuretic peptide decreased significantly from 3 days to 6 weeks in the large MI group and normalized in the small MI group (control, 25.0; small MI, 26.4; large MI, 44.4 pM). Plasma renin activity was not elevated at either time. However, the change in ANP from 3 days to 6 weeks in the MI rats was negatively related to the change in PRA (r = .48, P = .016). Atrial natriuretic peptide levels early after MI may be a good predictor of infarct size. The pattern of ANP and PRA changing in opposite directions over time suggest a counterregulatory link between these two systems.