Background: As the traditional indicators of the operative outcomes, including morbidity and mortality, cannot give sufficient information on a patient’s physical, mental, emotional, and functional well-being alone, we aimed to compare life quality in the patients under open vein harvesting (OVH) and endoscopic vein harvesting (EVH) techniques after four years of follow-up. Methods: This prospective cohort study followed all the patients who were scheduled for off-pump CABG in the Mashhad-based Imam Reza Hospital, in October 2013, for 4 years. Accordingly, data related to their quality of life were collected, and their life quality was then compared using the WHOQOL-BREF scale. T-test and relative risk were also used. Results: This study was conducted on a total of 103 patients under the two techniques of OVH (n = 53) and EVH (n = 50). The difference between the EVH (4.7%) and OVH (16.3%) groups at the demographic characteristics was the Transient Ischemic Attack (P = 0.023). After a 4-years follow-up period, no significant differences were observed between the patients undergoing the two techniques of OVH and EVH in all the domains of life quality. Conclusions: According to the obtained results, there was no difference in the quality of life between the patients undergoing OVH and EVH techniques over a four-year period. In this regard, further investigations are recommended on the quality of life in patients under the two techniques of OVH and EVH with long-term follow-up periods.