Background: A proportion of patients who meet the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Associations criteria for Alzheimer disease (AD) have frontotemporal lobar degeneration (FTLD) confirmed at autopsy, with or without concomitant AD. Thus, the clinical phenotypes of the 2 disorders may overlap. Objective: To identify clinical and psychometric indicators that distinguish AD from FTLD at initial presentation. Design: Longitudinal study of memory and aging. Setting: Alzheimer's Disease Research Center, Washington University School of Medicine. Participants: Forty-eight clinically well-characterized cases of autopsy-confirmed FTLD (27 with psychometric testing results) were compared with 27 autopsy-confirmed AD cases. Results: Behavioral abnormalities, particularly impulsivity (P<.001), disinhibition (P<.001), social withdrawal (P=.01), and progressive nonfluent aphasia, distinguished individuals with FTLD from those with AD. The individuals with FTLD performed better than those with AD on a visual test of episodic memory (P=.01), but worse on word fluency (P=.02) (performance correlated with aphasic features). Other cognitive and clinical features, including executive dysfunction and memory impairment, were comparable between the FTLD and AD groups. Concomitant histopathological AD was present in 11 of the 48 individuals with FTLD. Conclusions: Clinical and cognitive features of FTLD may overlap with AD, although behavioral and language difficulties distinguish those with FTLD. Memory loss in those with FTLD may in part reflect word-finding difficulties stemming from language dysfunction. Compounding the overlap of FTLD and AD clinical phenotypes is the presence of histopathological AD in almost one fourth of individuals with FTLD.