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Background: Emerging evidence shows sex differences in manifestations of neuropsychiatric symptoms (NPS) in memory clinic patients. NPS are common in patients with vascular cognitive impairment (VCI) affecting quality of life and caregiver burden, however sex differences are largely unknown. We aimed first to establish sex differences in the manifestation of NPS in memory clinic patients with possible VCI and second to investigate the association between different NPS and substantial cognitive decline stratified by sex. Method: We included 737 memory clinic patients (age 68.1±8.4; 45% female) from the prospective TRACE-VCI cohort study with possible VCI; cognitive complaints and vascular brain injury (moderate/severe white matter hyperintensities (n = 398), microbleeds (n = 317), lacunar (n = 167) and non-lacunar (n = 85) infarct(s), macrobleeds (n = 14)). Dementia was diagnosed in 405 and MCI in 197 patients. NPS were measured using the 12-item Neuropsychiatric Inventory (NPI) and dichotomized as present ≥1. Substantial cognitive decline was defined as change of CDR ≥1 or institutionalization (available for n=571 without advanced dementia at baseline). The association between NPS and cognitive decline was assessed with Cox proportional hazard models in females and males separate, adjusted for other NPS, age and clinical diagnosis. Result:We found no difference in age nor distribution of clinical diagnoses between the sexes. Males more often presented with agitation (29% versus 17%) and irritability (58% versus 46%), while females more often presented with anxiety (32% versus 25%, all p<0.05), the other 9 NPS (delusions, hallucinations, aggression, depression, anxiety, euphoria, apathy, disinhibition, aberrant motor behavior, sleep/night-time disturbances and appetite and eating abnormalities) did not differ between the sexes. During follow-up, occurrence of substantial cognitive decline was comparable between males (14%) and females (15%). In males, substantial cognitive decline was higher in the presence of apathy (HR 2.5, 95%CI;1.2-5.4) and aberrant motor behavior (HR 2.2, 95%CI;1.1-4.6) and lower in the presence of appetite and eating abnormalities (HR 0.4, 95%CI;0.2-0.9). In females, none of the NPS were associated with substantial cognitive decline. Conclusion:Pattern and predictive value of NPS differs by sex in memory clinic patients with VCI. Acknowledgment of these differences could direct interventions.