Although much research has been done on the impact of chronic illness on quality of life, still relatively little is known about the role of comorbidity. Given the growing number of (older) people with multiple chronic conditions, more information is needed on the effects of specific disease combinations for preventive purposes. In a nationwide representative sample of 1673 non-institutionalized chronic disease patients (recruited in 56 general practices) in The Netherlands, we assessed the separate and joint effects of cardiovascular disease, cancer, arthritis, chronic respiratory disease, diabetes mellitus, and thyroid dysfunction on physical and mental functioning. Data on medical diagnoses were provided by the general practitioners; data on physical and mental functioning were collected by a patient survey (SF-36). Compared to reference data of the general population, physical functioning appeared to be worse in all six diagnostic groups, whereas mental functioning was more or less comparable. Patients with arthritis or those suffering from comorbidity reported the lowest levels of physical functioning. Synergistic effects of combinations of diabetes, cardiovascular disease and/or chronic respiratory disease were found, indicating that patients suffering from these disease combinations run a higher risk of physical disability than could be expected from their separate effects.