BACKGROUND: Despite several studies on the mental health of medical students, there is insufficient research on long-term follow-ups. AIMS: To investigate the associated factors and changes in the quality of life and mental health of a group of medical students followed-up for three years. METHODS: An observational, prospective cohort study was conducted. Four classes were followed during the first three years of the medical course. The study included sociodemographic data, mental health data using the DASS-21 scale, and quality-of-life data using the WHOQOL-BREF scale. Linear regression models were used for analysis. RESULTS: A total of 201 (66.1%) medical students responded to both data collection waves after a three-year follow-up. Depressive symptoms(p <
0.002), anxiety(p = 0.037), and stress(p <
0.002) increased. Additionally, physical(p <
0.002), psychological(p <
0.002), and social(p = 0.003) quality of life decreased. Worse mental health at baseline and being a woman were associated with worse mental health after three years, while higher income at baseline was associated with better quality of life after three years. CONCLUSIONS: The mental health and quality of life of the medical students worsened after three years, being influenced by gender, income, and mental health at baseline. Educators and managers must be aware of these factors to minimize suffering in medical schools.