There are currently no Food and Drug Administration-approved treatments for frontotemporal lobar degeneration (FTLD). The objectives of this study were to explore the tolerability of memantine treatment in FTLD and to monitor for possible effects on behavior, cognition, and function. Forty-three individuals who met clinical criteria for FTLD [21 with frontotemporal dementia (FTD), 13 with semantic dementia (SD), and 9 with progressive nonfluent aphasia (PA)] received 26 weeks of open-label treatment with memantine at a target dose of 20 mg daily. Concurrent treatment with acetylcholinesterase inhibitors was prohibited. Cognitive and functional outcome measures included the Mini Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog), clinical dementia rating-sum of boxes, Neuropsychiatric Inventory (NPI), Frontal Behavior Inventory, Executive Interview (EXIT25), Texas Functional Living Scale (TFLS), Geriatric Depression Scale, and Unified Parkinson's Disease Rating Scale-motor scale. Most subjects were able to tolerate the target dose of memantine. A transient improvement was observed on the total NPI score primarily in the FTD group. Variable declines were observed on the ADAS-cog, EXIT25, Frontal Behavior Inventory, NPI, TFLS, and UPDRS scores. The FTD and SD groups declined on most of the cognitive and behavioral outcome measures, but remained stable on the UPDRS, whereas the progressive nonfluent aphasia group remained relatively stable on the ADAS-cog, NPI, and TFLS, but declined on the UPDRS. Memantine was well-tolerated in these subjects. Future placebo-controlled trials of memantine in FTLD are warranted and may have greater power to detect behavioral and cognitive effects if focused on the FTD and SD clinical syndromes.