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To examine the risk factors and comorbidities of hippocampal sclerosis (HS) in the oldest-old.A total of 134 participants with dementia from The 90+ Study with longitudinal evaluations and autopsy were included in this investigation. Participants were divided into 2 groups, one with and one without HS pathology, and differences in clinical and pathologic characteristics were compared.Persons with HS tended to have a longer duration of dementia compared to participants without HS (mean 4.0 years vs 6.7 years, odds ratio [OR] 1.26; 95% confidence interval [CI] 1.11–1.42; p < 0.001). HS was more likely in participants with a history of autoimmune diseases (rheumatoid arthritis or thyroid disease, OR 3.15; 95% CI 1.30–7.62; p = 0.011), high thyroid-stimulating hormone (OR 4.94; 95% CI 1.40–17.46; p = 0.013), or high thyroid antibodies (OR 3.45; 95% CI 1.09–10.88; p = 0.035). Lewy body disease (LBD) pathology was also associated with an increased likelihood of HS (OR 5.70; 95% CI 1.22–26.4; p = 0.027).We identified autoimmune conditions (rheumatoid arthritis and thyroid disease) as potential risk factors for HS in our cohort. LBD was the only pathology that was associated with increased odds of HS and those harboring HS pathology had a longer duration of dementia. This suggests multiple pathways of HS pathology among the oldest-old.