Introduction: Timely fibrinolysis for acute ST-segment elevation myocardial infarction (STEMI) reduces infarct size and hence preserves LV function and reduces mortality. Optimal regimen of streptokinase (SK) infusion in such patients is a matter of interest. The current study aimed to compare efficacy and safety of accelerated SK infusion regimen in patients with STEMI versus the standard one. Methods: One hundred consecutive STEMI patients were randomly allocated into one of 2 groups: group I (50 patients) who received accelerated SK regimen (1.5 million units over 30 minutes) and group II (50 patients) received standard SK regimen (1.5 million units over 60 minutes). Efficacy was evaluated non-invasively using clinical (chest pain), ECG (resolution of ST segment) and laboratory tests (earlier and higher peaking of cardiac troponin I). Safety was evaluated by assessment of multiple in-hospital adverse events. Results: Both groups were statistically matched in all baseline criteria. There was a significant difference between both groups regarding each parameter of successful reperfusion in favor of accelerated regimen. When all these parameters were combined, 31 patients (62%) had successful reperfusion in group I versus 19 patients (38%) in group II (P = 0.016). We did not report any significant difference between both groups regarding in-hospital mortality, in-hospital heart failure, major bleeding, hypotension or allergic reaction to SK. Mean pre-discharge ejection fraction was higher in group I than group II (50.9 ± 6.6% versus 47.3 ± 4.6%, P = 0.002). Conclusion: Accelerated regimen of SK infusion is safe and effective method of reperfusion in patients with STEMI.