Introduction: There is paucity of data about the possible role of ABO antigen in response to pharmacologic reperfusion therapy in ST-segment elevation myocardial infarction (STEMI) and its relationship with ST segment recovery; thus, we aimed to evaluate the association of ABO antigen with ST-segment resolution in STEMI patients treated with thrombolysis. Methods: This prospective and observational study was conducted between March 2016 and September 2017 on patients with first acute STEMI within the first 12 hours after onset of symptoms treated with thrombolysis. Myocardial reperfusion success was determined by single-lead ST-segment recovery in 12-lead ECG. Patients were considered as responders if ST-segment resolved ≥50% or were assigned as non-responders if ST-segment resolution was <50%. Univariable and multivariable analyses were performed to examine the contribution of "A" and "B" blood group antigens to ST-segment resolution and the occurrence of major adverse cardiovascular or cerebrovascular event (MACCE). Odds ratio (OR) with 95% confidence interval (CI) were reported for each variable. Results: In this study 303 patients (187 males and 116 females) with a mean age of 56.6 ± 16.8 (ranging from 39 to 87 years) were enrolled. 184 patients (60.7%) were responders and 119 patients (39.2%) were non-responders. The presence of either A (4.5 folds increase) or B (5.4 folds increase) antigen was associated with a higher likelihood of a response to thrombolytic therapy, while had not effect on the occurrence of MACCE. Conclusion: We conclude that the presence of A or B blood group antigens is associated with a better response to thrombolytic therapy in patients with acute STEMI. This finding may imply a higher likelihood for thrombotic occlusion of coronary arteries in patients who have either A or B antigen in their blood.