The aim of this study was to compare the quality of life of first and last-year medical students. A cross-sectional study was performed using the brief format of the World Health Organization instrument for evaluating quality of life (Whoqol-bref) in a sample of 370 medical students from Recife, Pernambuco State Brazil (229 first-year and 141 last-year students). According to the findings, scores from the psychological health domain were lower for last-year as compared to first-year students (p < 0,005). This difference remained after covariance analysis (Ancova). As for scores in the physical health domain, social relationships, and the environment, there were no significant differences between first and last-year students. For self-rated quality of life, first-year students showed better results (3,87 vs. 3,39; p < 0,001). There was no statistically significant difference in health-related self-satisfaction; 3,94 vs. 3,62 (p = 0,099). In conclusion, medical students' quality of life declines during medical school as measured by the Whoqol-bref psychological health domain. Further research is needed to identify the factors leading to these changes in quality of life among medical students during their undergraduate training.