Mental problems such as stress, anxiety and depression have been described among medical students and are associated with poor academic and professional performance. It has been speculated that these problems impair students' quality of life (QoL). The authors aimed to assess the health-related QoL (HRQL) of medical students throughout their 6 years of training at a school with a traditional curriculum. Of a total of 490 students attending our institution's medical school, 38 were surveyed in February 2006 (incoming Year 1 group, surveyed when students were in the second week of Year 1 classes) and 352 were surveyed in February 2007 (students in Years 1-6). Students self-reported their HRQL and depressive symptoms using the Short-Form Health Survey (SF-36) and the Beck Depression Inventory (BDI). Comparisons were performed according to year in training, presence of depressive symptoms, gender, living arrangements and correlations with family income. The students' ages ranged from 18 to 31 years (median 22.3 years). Students in Years 2, 3, 4 and 6 had lower scores for mental and physical dimensions of HRQL compared with the incoming Year 1 group (P < 0.01), with the largest difference observed for Year 3 students. Students with depressive symptoms had lower scores in all domains of the SF-36 (P < 0.01). Female students had lower HRQL scores than males (P < 0.01). No differences were observed for students living with versus without family and no correlation with family income was found. Major impairments in HRQL were observed among Year 3 students, students with depressive symptoms and women. Medical schools should institute efforts to ensure that students' HRQL and emotional support are maintained, particularly during critical phases of medical training.