We sought to determine the relative cost and effectiveness of two different reperfusion modalities in patients with acute myocardial infarction (AMI). Recent studies have found superior clinical outcomes after reperfusion by primary percutaneous transluminal coronary angioplasty (PTCA) compared with thrombolytic therapy. The high up-front costs of cardiac catheterization may diminish the relative advantages of this invasive strategy. Detailed in-hospital charge data were available from all 358 patients with AMI randomized to tissue-type plasminogen activator (t-PA) or primary PTCA in the United States from the Primary Angioplasty in Myocardial Infarction trial. Resource consumption during late follow-up was estimated by assessment of major clinical events and functional status. Compared with t-PA, primary PTCA resulted in reduced rates of in-hospital mortality (2.3% vs. 7.2%, p = 0.03), reinfarction (2.8% vs. 7.2%, p = 0.06), recurrent ischemia (11.3% vs. 28.7%, p < 0.0001) and stroke (0% vs. 3.9%, p = 0.02) and a shorter hospital stay (7.6 +/- 3.3 days vs. 8.4 +/- 4.7 days, p = 0.04). Despite the initial costs of cardiac catheterization in all patients with the invasive strategy, total mean (+/- SD) hospital charges were $3,436 lower per patient with PTCA than with t-PA ($23,468 +/- $13,410 vs. $26,904 +/- $18,246, p = 0.04), primarily due to the reduction in adverse in-hospital outcomes. However, professional fees were higher after primary PTCA ($4,185 +/- $3,183 vs. $3,322 +/- $2,728, p = 0.001), and thus total charges, although favoring PTCA, were not significantly different ($27,653 +/- $13,709 vs. $30,227 +/- 18,903, p = 0.21). At a mean follow-up time of 2.1 +/- 0.7 years, no major differences in postdischarge events or New York Heart Association functional class were present between PTCA- and t-PA-treated patients, suggesting similar late resource consumption. Including in-hospital events, 83% of PTCA-treated patients were alive and free of reinfarction at late follow-up, compared with 74% of t-PA-treated patients (p = 0.06). Compared with t-PA, reperfusion by primary PTCA improves clinical outcomes with similar or reduced costs. These findings have important clinical implications in an increasingly cost-conscious health care environment.