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Abstract Background: The purpose of this study was to clarify the correlations between the presence of comorbidities and psychological distress and health-related quality of life (HRQL). This was a population-based cross-sectional study. Methods: Parents and grandparents of students from seven randomly selected primary schools in the city centre were asked to answer questionnaires sent by their children. All subjects were questioned for somatic diseases, psychological distress and HRQL by Health Questionnaire, Hospital Anxiety and Depression scale and short-form-12 health survey, respectively. Results: Out of 5024 parents and grandparents (mean age 52.3 ± 14.3 years, range 20–104 years) of primary school students 4605 returned the questionnaires, a figure that corresponds to the overall response rate of 91.6%. Chronic diseases substantially reduced HRQL and this effect did not differ markedly with the type of chronic disease. Association of comorbidities with psychological distress further impaired HRQL. As the number of chronic diseases was increased, HRQL and physical and mental functioning declined. The worst HRQL was observed in subjects who had five or more comorbidities associated with psychological distress. Conclusion: The present study indicates significant adverse effects of chronic diseases and psychological distress on HRQL in adults, the effect of psychological distress being the most important. Our results lead us to suggest that in the management of comorbidities, the detection of the presence and severity of associated psychological distress and its treatment, besides the specific treatment of comorbidities, may provide dramatic improvement in HRQL of the patients.