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Objective: There is a paucity of large cohort-based evidence regarding the need and added value of diffusion-weighted imaging (DWI) in patients attending outpatient clinic for cognitive impairment. We aimed to evaluate the diagnostic yield of DWI in patients attending outpatient clinic for cognitive impairment. Materials and methods: This retrospective, observational, single-institution study included 3,298 consecutive patients (mean age ± SD, 71 years ± 10; 1,976 women) attending outpatient clinic for cognitive impairment with clinical dementia rating ≥ 0.5 who underwent brain MRI with DWI from January 2010 to February 2020. Diagnostic yield was defined as the proportion of patients in whom DWI supported the diagnosis that underlies cognitive impairment among all patients. Subgroup analyses were performed by age group and sex, and the Chi-square test was performed to compare the diagnostic yields between groups. Results: The overall diagnostic yield of DWI in patients with cognitive impairment was 3.2% (106/3,298; 95% CI, 2.6–3.9%). The diagnostic yield was 2.5% (83/3,298) for acute or subacute infarct, which included recent small subcortical infarct for which the diagnostic yield was 1.6% (54/3,298). The diagnostic yield was 0.33% (11/3,298) for Creutzfeldt-Jakob disease (CJD), 0.15% (5/3,298) for transient global amnesia (TGA), 0.12% (4/3,298) for encephalitis and 0.09% (3/3,298) for lymphoma. There was a trend towards a higher diagnostic yield in the older age group with age ≥ 70 years old (3.6% vs 2.6%, P =.12). There was an incremental increase in the diagnostic yield from the age group 60–69 years (2.6%; 20/773) to 90–99 years (8.0%; 2/25). Conclusion: Despite its low overall diagnostic yield, DWI supported the diagnosis of acute or subacute infarct, CJD, TGA, encephalitis and lymphoma that underlie cognitive impairment, and there was a trend towards a higher diagnostic yield in the older age group. [ABSTRACT FROM AUTHOR]