This study examined the effects of comorbid medical conditions (heart disease, pulmonary disease, hypertension and obesity) on the association of radiographic knee osteoarthritis (OA) with long-term difficulty in physical function. Data are from the National Health and Nutrition Examination Survey, 1971-1975 (NHANES I), a prospective epidemiologic cohort study, and the NHANES Epidemiologic Follow-up Study, 1982-1984 (NHEFS) and included 4059 persons who were 45-74 years old and participated in the detailed examination component of NHANES I. Knee OA was ascertained by anterior-posterior bilateral radiographs of the knee and self-report of knee pain, heart and pulmonary disease by self report of disease or symptoms, and hypertension and obesity by blood pressure and weight measurements. The presence of symptomatic knee OA at NHANES I was associated with reported difficulty at NHEFS 1982-84 in functions which used the lower extremity (ambulation and transfer). The presence of coexistent chronic conditions, particularly heart disease, pulmonary disease and obesity, increased the likelihood of subsequent disability. These findings suggest that knee OA is associated with long-term physical disability, and that the presence of coexistent chronic disease may increase the amount of long-term disability from knee OA.