Comorbid medical illnesses are a key feature of geriatric mood disorders, yet the specificity of such associations remains unclear. In a sample of 546 primary care patients age >or=65 years, pathology in several organ systems (respiratory, eye/ear/nose/throat, gastrointestinal, central nervous system, endocrine) and several chronic conditions (neurological disease, low vision, chronic obstructive pulmonary disease, diabetes) were associated with depression. However, notwithstanding these specific associations, global (overall) medical burden was most powerfully and independently associated with depression, largely independent of functional status. This generates the hypothesis that, in general primary care populations, the relationship of medical illness to depression may be multimodal and/or may involve shared pathobiological or psychosocial mechanisms.