Objectives: Medical students experience numerous demands during the education process, which determine their quality of life (QoL). In particular, the first years of medical studies are a challenge for students. This paper aims to identify and evaluate the quality of life with simultaneous assessment of their determinants in Polish medical students in Poland during longitudinal observation. Material and Methods: The authors analyzed data collected from the first follow-up of the cohort study named POLLEK (Polski Lekarz – The Polish Physician) conducted among medical students at the Medical University of Silesia in Katowice, Poland. The QoL was assessed using the abbreviated version of the World Health Organization Quality of Life Test – Bref (WHOQOL-BREF) questionnaire. Students were followed at 2 points of time: in their first year of studies – the academic year 2021/2022 (T1) (N = 427), and then in their second year – the academic year 2022/2023 (T2) (N = 335). Results: Changes in QoL indicators were analyzed using paired data. A significant decrease in the QoL scores in the somatic and psychological domain in T2 was observed, while scores in the environmental domain showed an increase by T2. In addition, it was found that better self-rated health (SRH), higher physical activity (PA), and better socioeconomic status (SES) were the key determinants of higher quality of life domains across both T1 and T2 domains. Conclusions: In conclusion, although the overall QoL remained stable throughout the observation period, the QoL in the somatic and psychological domains deteriorated among medical students between T1 and T2. However, there was a slight improvement in the environmental domain during the second year. The observations suggest that medical schools should actively promote a balance between schoolwork and the personal life of medical students, and courses on coping with difficult, stressful situations. These activities should be introduced at an early stage of medical education. Int J Occup Med Environ Health. 2024;37(5)