Despite much speculation about the relationship between depression and medical comorbidity in primary care settings, few investigators have examined this issue empirically. Using a two-stage screening procedure, we assessed 618 patients aged 18 to 64 years in an academic general medicine clinic. Forty-one patients (6.6%) suffered from a current episode of major depressive disorder (MDD). We compared this group with a 20% random sample of nondepressed patients. While patients with MDD were younger (mean age, 41.1 vs 47.2 years), they were assessed by the Duke University Severity of Illness Scale as having more severe medical illness. Patients with MDD were more likely to have malignant tumors and "ill-defined conditions" than nondepressed patients. The 18 patients with MDD (44%) who were correctly diagnosed by their physicians had less severe medical illness than those whose depression was clinically undetected. A logistic regression model predicting MDD group membership included female gender, younger age, higher Duke University Severity of Illness Scale score, and more frequent inactive ill-defined diagnoses. These findings are consistent with assertions: (1) patients with MDD have more physical illness than nondepressed patients and/or (2) somatic symptoms and disability caused by MDD add to the burden of physical illness.