Previous studies about the association of multimorbidity and the health-related quality of life (HRQOL) in primary-care patients are limited because of their reliance on simple counts of diseases from a limited list of diseases and their failure to assess the severity of disease. We evaluated the association while taking into account the severity of the medical conditions based on the Cumulative Illness Rating Scale (CIRS) score, and controlling for potential confounders (age, sex, household income, education, self-perception of economic status, number of people living in the same dwelling, and perceived social support). We randomly selected 238 patients to construct quintiles of increasing multimorbidity (CIRS). Patients completed the 36-item Medical Outcomes study questionnaire (SF-36) to evaluate their HRQOL. Applying bivariate and multivariate linear regression analyses, we used the CIRS as either a continuous or a categorical (quintiles) variable. Use of the CIRS revealed a stronger association of HRQOL with multimorbidity than using a simple count of chronic conditions. Physical more than mental health deteriorated with increasing multimorbidity. Perceived social support and self-perception of economic status were significantly related to all scales of the SF-36 (p < 0.05). Increased multimorbidity adversely affected HRQOL in primary-care adult patients, even when confounding variables were controlled for.