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Abstract Background Coronary physiology-guided PCIs are recommended worldwide. However, invasive coronary physiology methods prolong the procedure, create additional risks for the patients, and prolong the fluoroscopy time for an interventional cardiologist. Otherwise, there is a noninvasive coronary physiology evaluation method, QFR, that can be safely used even in STEMI patients. Methods A total of 198 patients admitted with STEMI and at least one intermediate (35–75%) diameter stenosis other than the culprit artery between July 2020 and June 2021 were prospectively included in this single-center study. All patients were randomized into one of two groups (1 - QFR-guided PCI; 2 - visual-estimation-only guided PCI). A 12-month follow-up with echocardiography, exercise stress test, and quality of life evaluation was performed in all included patients. For the QOF evaluation, the Seattle Angina Score Questionnaire was chosen. Statistical analysis was performed using the Kolmogorov–Smirnov test, Student’s t-test, Mann–Whitney U test, Pearson’s chi-squared test and Kaplan–Meier estimator. Results Ninety-eight (49.5%) patients were randomized to the first group, and 100 (50.5%) patients were included in the second group. Statistically, significantly more patients had a medical history of dyslipidemia (98 vs. 91, p = 0.002) and slightly better left ventricular ejection fraction (42.21 ± 7.88 vs. 39.45 ± 9.62, p = 0.045) in the QFR group. Six fewer patients required non-culprit artery revascularization within the 12-month FU in the QFR group (1.02% vs. 6%, p = 0.047). Survival analysis proved that patients in the Angio group had a more than 6-fold greater risk for death within a 12-month period after MI (OR 6.23, 95% CI 2.20-17.87, p = 0.006), with the highest mortality risk within the first two months after initial treatment. Conclusion Using QFR in non-culprit lesions in patients with ST-elevation myocardial infarction reduces mortality and revascularization at the 12-month follow-up and improves the quality of life of the patient. Trial registration The study was approved by the Regional Bioethical Committee and conducted under the principles of the Helsinki Declaration and local laws and regulations.