Background: Despite the increased risk, the quality of somatic healthcare is lower for patients with mental illnesses. Currently dominant approach separates physical and mental, primary and secondary healthcare. Objective of our study was to explore whether somatic comorbidities are associated with a poor HRQoL independently of some sociodemographic and clinical factors. Majority of studies have explored particular somatic and psychiatric illnesses. Therefore we decided to access the problem from the general perspective of the universe of somatic and mental illnesses in the large psychiatric institution. Subjects and methods: This nested cross-sectional study was done during May 2016 at Psychiatric hospital Sveti Ivan, Zagreb, Croatia on the sample of 506 patients diagnosed with psychiatric illnesses (ICD-10: F00-F99). Key outcome was the lowest 25% results on the SF-36 General health sub-scale, indicating the worst HRQoL. Predictors were all detected somatic illnesses. By multivariate logistic regression we controlled different sociodemographic, vital and clinical factors. Results: After adjustment for different sociodemographic and clinical factors, three somatic comorbidities remained independently associated with the worst HRQoL: endocrine, nutritional and metabolic diseases (E00-E90), diseases of respiratory system (J00-J99) and diseases of musculoskeletal system and connective tissue (M00-M99) Conclusions: Somatic comorbidities in psychiatric patients are associated with the poor HRQoL independently of different sociodemographic, vital and clinical factors and they should be treated seriously and integrally with mental aspects of HRQoL. Early comorbidities detection and adequate pharmacological and psychotherapeutic treatment, as well as the prevention of risk factors, may improve the quality of life and reduce morbidity and mortality of psychiatric patients.