BACKGROUND: A significant percentage of patients with major depressive disorder (MDD) suffer from concurrent general medical conditions (GMCs). OBJECTIVE: The objective of this preliminary report was to describe the rates of co-occurring significant GMCs and the clinical correlates and symptom features associated with the presence of GMCs. DESIGN: Baseline cross-sectional case-control study of patients enrolling in a prospective randomized multistage treatment study of MDD. SETTING: Fourteen regional U.S. centers representing 19 primary care and 22 psychiatric practices. PATIENTS: One thousand five hundred outpatients with DSM-IV nonpsychotic MDD. MEASUREMENTS: Sociodemographic status, medical illness ratings, psychiatric status, quality of life and DSM-IV depression symptom ratings. RESULTS: The prevalence of significant medical comorbidity in this population was 52.8% (95% CI 50.3-55.3%). Concurrent significant medical comorbidity was associated with older age, lower income, unemployment, limited education, longer duration of index depressive episode and absence of self-reported family history of depression. Somatic symptoms common in MDD were endorsed at a higher rate in those with GMCs. Those without a GMC had higher rates of endorsement of impaired mood reactivity, distinct mood quality and interpersonal sensitivity. CONCLUSIONS: Concurrent GMCs are common among outpatients with MDD in both primary care and specialty settings. Concurrent GMCs appear to influence the severity and symptom patterns in MDD and describe a vulnerable population with sociodemographic challenges to effective assessment and treatment.