Abstract Background Sustainability of methadone maintenance treatment (MMT) program involves regularly assessing its impact on health and social outcomes of drug users in different settings, particularly in disadvantaged areas. In this study, we evaluated the change in quality of life (QoL), and identified associated factors amongst drug users over the course of 12-month MMT in Vietnamese mountainous provinces. Methods We conducted a longitudinal study among patients from 6 MMT clinics in three mountainous provinces of Vietnam. At baseline, we screened 300 participants and after a 12-month treatment, 244 participants remained to involve in the study. World Health Organization Quality of Life short form instrument (WHOQOL-BREF) was used to measure the QoL of patients. The magnitude of the changes was extrapolated. Results There were significant changes in all four dimensions of quality of life measured by WHOQoL-BREF between baseline and 12 months with the effect size ranged from 0.21 to 0.24. Increased age, being workers compared to unemployment and having health problems or comorbidities were positively related to reduced scores of QoL. Conclusions To conclude, we observed a significant increase in the QoL level regarding physical, psychological, social relationships and environmental aspects among people who used drug after 12 months of MMT. Findings from this study emphasize the role of continuously receiving MMT treatment among people using drugs to enhance their QoL.