BACKGROUND: Mental distress is a mental health problem expressed with variable levels of depressive, anxiety, panic or somatic symptoms. Owing to several factors tertiary level students are among the population with higher prevalence of mental distress and an even more higher prevalence has been reported in medical students. The aim of this study was to determine the prevalence of mental distress among medical students, and to evaluate contextually relevant associated factors. METHODS: A cross-sectional study was conducted among medical students attending Hawassa University College of Medicine and Health Sciences in 2013/2014 academic year. Stratified random sampling was implemented with each strata representing the year of study of the students. Data on mental distress was collected using the Self-Reporting Questionnaire-20 (SRQ-20). Data was entered into and analyzed using IBM SPSS statistics 21. A cut-off point of 8 and above was used to classify students as having mental distress. RESULTS: Among 240 students included in the study, 72 (30%) of them were found to have mental distress. There was no significant difference in mental distress between males and females (COR = 1.18, 95% CI = 0.62-2.25). On bivariate analysis, students with age less than or equal to 21 years showed higher odds of having mental distress (COR = 2.3, 95% CI: 1.26-4.22), but because of having high correlation with students' year of study, age was excluded from the multivariate model. In this study being a pre-medicine student (AOR = 3.61, 95% CI: 1.45-8.97), perceiving medical school as very stressful (AOR = 3.89, 95% CI: 1.52-9.94), perceiving living environment as very crowded (AOR = 2.43, 95% CI: 1.24-4.77) and having a feeling of insecurity about one's safety (AOR = 2.93, 95% CI: 1.51-5.68) had statistically significant association with mental distress. CONCLUSIONS: In this study one-third of medical students were found to have mental distress. Designing prevention and treatment programs to address contextually relevant factors is very important.