This study investigates the association between regional and global p-tau pathology in chronic traumatic encephalopathy (CTE) and various cognitive, functional, and neuropsychiatric symptoms. The sample included 364 brain donors with autopsy-confirmed CTE, predominantly former American football players. P-tau severity was assessed in 10 cortical and subcortical regions, and informant-completed scales were used to evaluate cognition, daily function, neurobehavioral dysregulation, depression, and apathy. Global p-tau severity was associated with worse cognitive and functional symptoms, while regional p-tau severity in the frontal cortex, inferior parietal cortex, superior temporal cortex, and amygdala was significantly associated with cognitive and functional impairments. The frontal cortex was also the strongest contributor to neurobehavioral dysregulation. These findings suggest that p-tau aggregates, particularly in the frontal cortex, are key determinants of cognitive and functional difficulties in CTE. The study highlights the importance of regional p-tau pathology in understanding the clinical features of CTE and can inform future diagnostic criteria and interventions.This study investigates the association between regional and global p-tau pathology in chronic traumatic encephalopathy (CTE) and various cognitive, functional, and neuropsychiatric symptoms. The sample included 364 brain donors with autopsy-confirmed CTE, predominantly former American football players. P-tau severity was assessed in 10 cortical and subcortical regions, and informant-completed scales were used to evaluate cognition, daily function, neurobehavioral dysregulation, depression, and apathy. Global p-tau severity was associated with worse cognitive and functional symptoms, while regional p-tau severity in the frontal cortex, inferior parietal cortex, superior temporal cortex, and amygdala was significantly associated with cognitive and functional impairments. The frontal cortex was also the strongest contributor to neurobehavioral dysregulation. These findings suggest that p-tau aggregates, particularly in the frontal cortex, are key determinants of cognitive and functional difficulties in CTE. The study highlights the importance of regional p-tau pathology in understanding the clinical features of CTE and can inform future diagnostic criteria and interventions.