Objectives: Postconditioning has been reported to reduce infarct size in ST-segment myocardial infarction (STEMI). However, recently, few other studies did not show any effect of postconditioning and suggested that it may be even harmful. We sought to assess whether postconditioning could reduce infarct size and improve myocardial reperfusion in early presenters with STEMI. Methods: 72 STEMI patients treated with primary percutaneous coronary intervention (PCI) were randomly assigned to either the postconditioning (n = 35) or the standard PCI group (control group; n = 37). Blood samples were obtained for creatine kinase (CK) and its MB isoform (CK-MB) within 36 h. The angiographic (myocardial blush grade, MBG) and electrocardiographic (ST-segment resolution, STR) data were evaluated and compared between groups. Results: The areas under the curve of CK and CK-MB release were significantly reduced in the postconditioning group compared with the control group (38,612.91 ± 25,028.42 vs. 60,547.30 ± 25,264.63 for CK and 5,498.23 ± 3,787.91 vs. 7,443.12 ± 3,561.13 for CK-MB, p < 0.0001). MBG was significantly better in the postconditioning group than in the control group (MBG 3: 82.3 vs. 47.1%, p = 0.0023). In the postconditioning group, STR >70% was more often observed (97.1 vs. 64.1%, p = 0.0007). Conclusions: In patients with STEMI, postconditioning could significantly reduce enzymatic infarct size and improve myocardial reperfusion.