Background: Several trials suggested superiority of primary percutaneous coronary intervention (PPCI) angioplasty over thrombolysis in patients with ST-elevation myocardial infarction (STEMI), but many trials were characterized by low rates of early revascularization in patients treated with initial thrombolysis. We tested the hypothesis that in patients with hemodynamically stable STEMI, initial thrombolysis followed by an active early rescue/definitive revascularization strategy could achieve salutary short- and long-term outcomes. Methods: A prospective registry documented all 212 STEMI patients who received initial thrombolytic therapy over a 2-year period in a single medical center. Median patient age was 58 (range: 29–92) years, 47 (22%) patients were aged >70 years and 18 (8%) >80 years. Fifty-two (25%) patients underwent rescue angioplasty <6 h after thrombolysis for inadequate clinical reperfusion. In 194/212 (92%) patients, coronary angiography was performed during initial hospitalization, PCI in 168 (79%), and coronary bypass surgery in 18 (8%). Results: Thirty-day mortality was 4.7% and 1-year mortality 6.7%. Mortality was not related to diabetes mellitus, hypertension, anterior infarction location, fibrin-specific thrombolytic drug or rescue PCI. By multivariate analysis, in-hospital definitive angiography/revascularization (p < 0.0001) and TIMI risk score >3 on admission (p < 0.01) were significant independent predictors of both 30 day and 12 month outcome. Conclusions: Initial thrombolysis was useful and effective in real-world STEMI patients when coupled with an aggressive policy of rescue angioplasty and early in-hospital revascularization. Outcomes compared favorably with those reported for PPCI trials. The adverse prognosis in older patients with higher TIMI risk score suggests that in those patients alternative initial treatment strategies such as PPCI should be considered.