Background: It has been determined in animal models that hyperoxia-induced preconditioning could reduce the ischemia/reperfusion injury of the heart tissue. Short-term ischemia and the subsequent reperfusion occur unavoidably in coronary angioplasty. The purpose of the present study was to determine the possible effects of oxygen pretreatment in inducing preconditioning during percutaneous transluminal coronary angioplasty (PTCA). Methods: Thirty-two patients, referred for elective angioplasty, were randomly divided into the control group and the oxygen group. The subjects in the oxygen group were exposed to normobaric oxygen (nearly 70% O2) via non-rebreathing masks for 1 hour at 12 and 2 hours before PTCA. One hour after the last oxygen pre-exposure period, the patients underwent PTCA (20 s of balloon inflation and 2 min of reperfusion). The chest pain score and cardiac injury biomarkers were assessed 12 hours after coronary angioplasty. The biomarker data and the chest pain scores were analyzed using the Mann–Whitney test and the Wilcoxon t- test. Also, the ratio of patients with positive C-reactive protein results was compared between the groups using the Fisher exact test. Results: The troponin I and CKMB levels were elevated in both groups after angioplasty, but there was no significant difference between the groups in this regard (P=0.23 and P=0.47, respectively). The average pain score during balloon inflation in the oxygen group was lower than that in the control group (2.8±1.2 vs. 4.11±1.21; P=0.008). Conclusions: Two episodes of 1-hour pre-exposure to normobaric hyperoxia (nearly 70% O2) at 12 and 2 hours before PTCA had no significant effect on myocardial injury biomarkers, troponin I, and CKMB. (Iranian Heart Journal 2016; 17(3):18-26)