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Background: Chronic fatigue syndrome (CFS) and depression are specific mental disorders that can negatively affect college students’ social, occupational, and academic performance, especially medical students. This study aimed to investigate the prevalence of CFS and depressive symptoms and their relationship with medical students. Methods: This cross-sectional analytical study was conducted with 175 medical students at the Guilan University of Medical Sciences in 2020 in Guilan in the north of Iran. Three levels of medical students, including basic sciences and physiopathology, externship, and internship students, participated. A demographic information questionnaire, the Beck Depression Inventory-II (BDI-II), and the Chalder Fatigue Questionnaire (CFQ) were used to collect data. SPSS 22 was used to analyze the data, including Mann-Whitney, KruskalWallis, and Spearman tests. Results: The mean age of the participants was 23.92 ± 2.04 years. Of 175 participants, 50.9% were males. In all, 11.4% of subjects reported levels of CFS, and 38.8 % of them showed levels of depression. The rates of CFS and depressions were not associated with age, gender, marital status, educational level, geographic area, or student habitation (P>0.05). The use of cigarettes (P=0.002), alcohol, and substances (P |