The purpose of this study was to define the sequential changes in left and right ventricular ejection fraction (LVEF, RVEF) and regional LV wall motion following first transmural acute myocardial infarction (AMI). Fifty-four patients with either anterior (n = 28) or inferior (n = 26) infarction underwent radionuclide ventriculography (RNV) within 48 hours of onset of chest pain (study 1), between days 3 and 6 (study 2), and again between days 7 and 25 (study 3). Twenty-six of the patients with anterior MI (93%) had initial LVEF less than 0.54, compared with 13 of 26 patients (50%) with inferior MI (p less than 0.01). Eleven of 26 patients (42.3%) with inferior MI had initial RVEF less than 0.39, compared with 8 of 27 patients (29.6%) with anterior MI (p less than 0.01). There were no overall significant serial changes in mean LVEF or mean RVEF in patients with either anterior or inferior MI. From study 1 to study 2, LVEF did not change in 24 patients (44%), improved in 13 (24%), and worsened in 17 (31%). From study 1 to study 3, LVEF remained unchanged in 15 patients (35%), improved in 17 (39%), and worsened in 11 (26%). From study 1 to study 2, RVEF did not change in 25 of 51 patients (49%), improved in 17 (31%), and worsened in 9 (17%). From study 1 to study 3, RVEF remained unchanged in 14 (38%), improved in 18 (48%), and worsened in five (14%). Changes in EF tended to occur early in the hospital course, with little subsequent changes. Serial changes in EF could not be predicted by clinical or demographic variables or by location of infarction. Significant changes in LVEF typically occurred without concurrent change in regional LV wall motion, suggesting alteration in ventricular loading rather than change in intrinsic myocardial performance. Initial depression of LVEF correlated with in-hospital mortality as well as with development of congestive heart failure and conduction defects. However, sequential changes in LVEF did not correlate with short-term prognosis. We conclude that sequential changes in LVEF and RVEF occur frequently following AMI, appear to reflect ventricular loading conditions rather than intrinsic change in myocardial performance, and do not correlate well with short-term prognosis.