Objectives: To compare health-related quality of life (QoL) of medical students in initial and final phases of the program, and to evaluate the association between ego defense mechanisms and specific healthrelated QoL domains within each group. Methods: This was an observational, cross-sectional study. Quality of life was assessed according to the World Health Organization Quality of Life instrument - Abbreviated Version (WHOQOL-Bref); anxiety and depression symptoms were evaluated using the Hospital Anxiety and Depression Scale (HADS); defense mechanisms were assessed using the Defense Style Questionnaire (DSQ-40). Results: A total of 139 medical students were evaluated. Students in the initial semesters of the program (1st and 3rd) presented more depressive symptoms and worse quality of life in the psychological domain of WHOQOL-Bref when compared to those in the final semesters (8th and 12th). In a later analysis, conducted to identify the variables associated with the psychological domain of the WHOQOL-Bref for each group, both depressive symptoms and defense mechanisms were independently associated with the outcome for medical students in the beginning and in the end of the graduation program. Conclusions: Students in the initial phases of medical school may need more specific attention from educational managers. Understanding the role of ego defense mechanisms in the quality of life of medical students may help identify effective psychopedagogical interventions for this population. In addition, the results reinforce the impact of depressive symptoms on quality of life, an association already well evidenced in the literature.