Allopurinol may have protective effects over ischemic reperfusion injury and reduce infarct size. In this randomized study, we aimed to evaluate the impact of allopurinol in patients with acute ST elevation myocardial infarction (STEMI) undergoing thrombolytic therapy. Overall, 140 patients with STEMI were randomly assigned to receive 400 mg of allopurinol or placebo before treating with streptokinase. Then, study group received 100 mg of allopurinol daily for 28 days and placebo group received placebo for the same period. ST resolution rate in 90 minutes, in-hospital mortality, and major adverse cardiac events (MACE) were compared. Compared to placebo group, patients receiving allopurinol had significantly higher rate of ST resolution rate ≥50% (68.8% vs. 50%, P = 0.04) and lower levels of peak Creatine kinase (CK) (P = 0.003), Creatine Kinase-MB (CK-MB) (P = 0.005), and Cardiac Troponin I (CTnI) (P < 0.001). Also, patients in allopurinol group had significantly lower rate of in-hospital MACE (P = 0.03), but there was no significant difference between groups regarding in-hospital mortality and cardiac events. In patients admitted with STEMI who are candidates of thrombolytic therapy, allopurinol is associated with better 90-minute ST resolution, lower enzymatically determined infarct size, and in-hospital MACE. More powerful studies are needed to determine the effect on mortality.