Background/Aim. Homelessness is a problem with social, medical, economic, political and other implications. Despite a large number of studies, reports about health-related quality of life (HRQoL) of homeless persons remain sparse. There is a summary of consistent evidence that homeless people have higher prevalence of chronic disease (mental and somatic) than general population. The aim of this study was to assess HRQoL and depression in homeless persons in Belgrade, to describe their sociodemographic factors and health status (the presence of chronic mental and somatic diseases and addiction disorders) and analyse impact of sociodemographic factors and health status to HRQoL and depression of homeless persons. Methods. The study was conducted in the Shelter for Adult and Elderly Persons in Belgrade, from January 1 to January 31, 2012. A set of questionnaires used in survey included Serbian translation of SF-36 questionnaire, Serbian translation of Beck Depression Inventory-II (BDI-II) and sociodemographic questionnaire. Statistical analysis was performed by descriptive and analytic methods. Results. Our study sample consisted of 104 adult participants. The majority of them were male (74%) and the mean age in the sample was 48.2 ± 13.0 years. We have found that 35.6% participants had lifetime diagnosis of psychiatric disorder, most frequently depression (lifetime prevalence of 15.4% in the study group). The history of suicide attempts was registered in 28 (26.9%) participants. Lifetime illicit drugs use was reported by 12.5%, daily smoking by 82.7% and daily alcohol consumption by 8.7% of the participants. Most common somatic chronic diseases were cardiovascular while chronic lung diseases were the second most frequent. Single chronic disease was present in 33 (31.7%) of the participants and comorbidity of 2 chronic diseases was present in 20 of them. A statistically significant difference between participants` HRQoL SF-36 domain scores and norms of general population was found only for role physical domain (lower in homeless, p < 0.001). ANOVA showed no statistically significant difference in SF-36 HRQoL domain and composite scores between different age groups, nor did marital status, education level, length of homelessness, alcohol use or smoking significantly affect the HRQoL. The mean BDI-II score in the studied population was 19.1 ± 11.6. Severe depression was registered in 20.2% of the participants, moderate in 23.1%, mild in 19.2% and minimal in 37.5%. A highly significant negative correlation was verified between BDI-II and all domains and composite scores of SF-36 (p < 0.001). Conclusion. Measures for prevention of homelessness should include: foundation of national registry of homeless persons, development of systemic multisectorial cooperation and special psychosocial intervention strategies. In homeless population, health care measures should be focused on prevention and treatment of mental health disorders and chronic somatic diseases.