A substantial portion of elderly patients admitted for inpatient rehabilitation treatment evidence cognitive dysfunction. Frequently, such patients also present with considerable medical comorbidity, that is, multiple concurrent illnesses. Identifying the potential role of cumulative illness in the etiology of cognitive decline in this group of frail elderly is limited by a lack of empirical information as little is known about this relationship. The goal of the present research was thus to investigate the relationship between cumulative illness and cognitive dysfunction while controlling for age and neurological and psychiatric symptomatology as these are previously known to affect cognitive function. Results indicate that cumulative illness predicts neuropsychological decline beyond the effects attributable to advanced age, mood, neurological pathology and psychiatric impairments. Even mild illness, if cumulative across several physical systems, can be predictive of cognitive deficits in this frail population. Of 11 organ systems studied, impairment of the vascular system was associated with the most diffuse profile of declined neuropsychological performance. Performances on measures of reasoning and judgment showed the strongest associations with cumulative illness. Implications of findings for neuropsychological diagnosis and prognosis are reviewed.