Background: Although primary percutaneous intervention (PCI) is the preferred reperfusion strategy in patients with STEMI, not all patients are good candidates for PCI—mainly because of a delay in requesting medical care and longer 1st medical contact to balloon time. The objective of this study was to compare the efficacy and side effects of 2 known fibrinolytic therapies, streptokinase (SK) and tenecteplase (TNK). Methods: This descriptive, analytic cross-sectional study recruited patients not amenable to primary PCI. a total of 142 patients recruited, 88 patients received SK and the other 54 patients received TNK. Thereafter, the efficacy of the agents, their side effects, territory of the culprit vessel, minor and major bleeding, relation to diabetes mellitus, and mortality in the index hospitalization were compared. Results: Patients who were administered SK showed a 2.09-mm ST elevation after the drug administration as opposed to 1.95 mm in the TNK group (P=0.340). Minor bleeding was reported in 22.7% of the SK group and 24.1% in the TNK group. Major bleeding in the SK and TNK groups was 11.1% and 5.7%, respectively, with no significant difference. In the patients’ index admission, death due to STEMI occurred in 10 (11.4%) patients in the SK group and 8 (14%) patients in the TNK group; the difference did not constitute statistical significance. Conclusions: The results of our study showed that SK and TNK were similar in terms of major complications, mortality rates, and efficacy. Thus, if TNK is not available, SK would be a reasonable choice. (Iranian Heart Journal 2017; 18(2):43-49)