Aim To compare the medium-term clinical efficacy and safety of 2-staged hybrid coronary revascularization versus percutaneous coronary intervation (PCI) in treatment of coronary heart disease patients with multivessel disease. Methods A prospective randomized controlled study was adopted from January 2012 to June 2016. 106 patients with coronary artery disease were selected as hybrid coronary revascularization (HCR group):the anterior descending branch was treated with minimally invasive direct coronary artery bypass (MIDCAB), and the other coronary artery branch lesions were treated by simple PCI 7 days after the operation. 106 patients with multiple coronary artery disease were selected as PCI group by using the propensity score methodology and matched with the clinical baseline features, the coronary artery lesions were treated with PCI alone. Follow up was performed at 1,3, 6,9, 12 months and 2 years after operation, and the major adverse cardiovascular and cerebrovascular events (MACCE) and secondary endpoints were recorded. The SYNTAX score and EuroSCORE were used to evaluate the complexity and degree of risk of coronary artery disease 2 years after operation, and to evaluate the 2 year target vascular patency rate; Kaplan-Meier method was used to compare the incidence of MACCE and target vascular smooth survival time in the two groups during the follow-up period, and cardiac function indexes including echocardiography parameters,Bü type natriuretic peptide and 6 min walking distance were evaluated 2 years after operation. Results The follow-up time was 2.3 years, the average was 18.2±8.3 months. The incidence of MACCE in HCR group and PCI group was 9.5% and 25.9% (P＝0.035), and the revascularization rate of HCR group was lower than that of PCI group (4.8% vs. 11.5%, P＝0.038). There was no significant difference in myocardial infarction, cerebrovascular accident, major bleeding events and death (P＞0.05); the all-cause mortality of HCR group was 0.9%, and that of PCI group was 4.8% (P＝0.104). The 2 year survival rate in HCR group was 99.1%, and that in PCI group was 95.2% (P＝0.532). The incidence of acute heart failure and recurrent angina in HCR group was lower than that in PCI group (P＝0.048 or P＝0.011). Kaplan-Meier method was used to compare the survival time of MACCE in the two groups after 2 year follow-up, the incidence of MACCE in HCR group was lower than that in PCI group (P＝0.003). At the end of the 2 year follow-up, the total CAG reexamine rate of the two groups was 90.1%. The target vascular patency rate in HCR group was 94.6% in the medium-term of 2 year follow-up after operation, which was higher than 84.5% of the PCI group (P＝0.037). 2 years after operation, the target vascular patency rate in HCR group was higher than that in PCI group (P＝0.042), SYNTAX score in HCR group was lower than that in PCI group (12.2±3.1 vs. 19.6±4.8, P＜0.001), and EuroSCORE in HCR group was lower than that in PCI group (2.2±1.1 vs. 2.7±1.3, P＝0.031), LVEF in HCR group was higher than that in PCI group (63.3%±9.4% vs. 60.1%±8.5%, P＝0.029), LVEDD and LVESD in HCR group were lower than those in PCI group (P＝0.043 and P＝0.037), and 6 min walking distance in HCR group was higher than that in PCI group (496±57 m vs. 413±413 m, P＝0.042). Conclusion Compared with PCI, the incidence of adverse events was lower during the 2 year follow-up of multiple coronary artery disease patients treated with 2-staged hybrid coronary revascularization, and the target vascular patency rate was higher.