BACKGROUND Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases associated with TAR DNA-binding protein 43- and ubiquitin-immunoreactive pathologic lesions. OBJECTIVE To determine whether survival is influenced by symptom of onset in patients with frontotemporal dementia and amyotrophic lateral sclerosis. DESIGN, SETTING, AND PATIENTS Retrospective review of patients with both cognitive impairment and motor neuron disease consecutively evaluated at 4 academic medical centers in 2 countries. MAIN OUTCOME MEASURES Clinical phenotypes and survival patterns of patients. RESULTS A total of 87 patients were identified, including 60 who developed cognitive symptoms first, 19 who developed motor symptoms first, and 8 who had simultaneous onset of cognitive and motor symptoms. Among the 59 deceased patients, we identified 2 distinct subgroups of patients according to survival. Long-term survivors had cognitive onset and delayed emergence of motor symptoms after a long monosymptomatic phase and had significantly longer survival than the typical survivors (mean, 67.5 months vs 28.2 months, respectively; P < .001). Typical survivors can have simultaneous or discrete onset of cognitive and motor symptoms, and the simultaneous-onset patients had shorter survival (mean, 19.2 months) than those with distinct cognitive or motor onset (mean, 28.6 months) (P = .005). CONCLUSIONS Distinct patterns of survival profiles exist in patients with frontotemporal dementia and motor neuron disease, and overall survival may depend on the relative timing of the emergence of secondary symptoms.