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Diabetes is rapidly increasing in prevalence among working-age adults, but little is known about the clinical characteristics that predict work disability in this population. This study assessed clinical predictors of work disability among working-age individuals with diabetes.In a cohort of diabetic individuals (n = 1,642) enrolled in a large health maintenance organization, excluding homemakers and retirees, we assessed the relation of diabetes severity, chronic disease comorbidity, depressive illness, and behavioral risk factors with work disability. Three indicators of work disability were assessed: being unable to work or otherwise being unemployed; missing ≥5 days from work in the prior month; and having severe difficulty with work tasks.In the study population, 19% had significant work disability: 12% were unemployed, 7% of employed subjects had missed ≥5 days from work in the prior month, and 4% of employed subjects reported having had severe difficulty with work tasks. Depressive illness, chronic disease comorbidity, and diabetes symptoms were associated with all three types of work disability. Diabetes complications predicted unemployment and overall work disability status, whereas obesity and sedentary lifestyle did not predict work disability. Among subjects experiencing both major depression and three or more diabetes complications, >50% were unemployed; of those with significant work disability, half met the criteria for major or minor depression.Depressive illness was strongly associated with unemployment and problems with work performance. Disease severity indicators, including complications and chronic disease comorbidity, were associated with unemployment and overall work disability status. Effective management of work disability among diabetic patients may need to address both physical and psychological impairments.