Psychological distress may decrease adherence to medical treatments and lead to poorer health outcomes of chronic diseases. The aim of this study was to evaluate the relationship between psychological distress and multimorbidity among patients seen in family practice after controlling for potential confounding variables and taking into account the severity of diseases. We evaluated 238 patients to construct quintiles of increasing multimorbidity based on the Cumulative Illness Rating Scale (CIRS), which is a comprehensive multimorbidity index that takes into account disease severity. Patients completed a psychiatric symptom questionnaire as a measurement of their psychological distress. In the first model of logistic regression analyses, we used the counted number of chronic diseases as the independent variable. In subsequent models, we used the quintiles of CIRS. After adjusting for confounding factors, multimorbidity measured by a simple count of chronic diseases was not related to psychological distress (OR, 1.12; 95% CI, 0.97-1.29; P = .188), whereas multimorbidity measured by the CIRS remained significantly associated (OR, 1.67; 95% CI, 1.19-2.37; P = .002). The estimate risk of psychological distress by quintile of CIRS was as follows: Q1/2 = 1.0; Q3 = OR, 1.72; 95% CI, 0.53-5.86; Q4 = OR, 2.99; 95% CI, 1.01-9.74; Q5 = OR, 4.67; 95% CI, 1.61-15.16. Psychological distress increased with multimorbidity when we accounted for disease severity. Clinicians should be aware of the possible presence of psychological distress, which can further complicate the comprehensive management of these complex patients.