Chronic medical conditions drastically affect the lives of those afflicted, leading to pain, disability, and disruption. Comorbid depression can exacerbate the effects of medical illness and may be an independent source of suffering and disability. Data from the Epidemiological Follow-Up Study (NHEFS) of the first National Health and Nutrition Examination Survey (NHANES I) are used to examine the manner in which depression and comorbid medical conditions interact to affect health-related quality of life (HRQOL). The findings suggest a) that the effects of depression are comparable with those of arthritis, diabetes, and hypertension; and b) that depression and chronic medical illnesses interact to amplify the effects of the medical illness. The data also support the merit of adopting a multidimensional approach to HRQOL rather than treating it unidimensionally.