AbstractA third of dementia cases could be attributable to modifiable risk-factors. Midlife high-density lipoprotein cholesterol (HDL-C) is a measure which could help identify individuals at reduced risk of developing age-related cognitive decline. The Japan Public Health Centre-based prospective (JPHC) Study is a large population-based cohort which started in 1990. This study included 1299 participants from Saku area in Nagano prefecture. Participants had HDL-C measured in 1995–1996, and underwent a mental health screening in 2014–2015. Of these, 1114 participants were included in MCI analyses, and 781 participants were included in dementia analyses. Logistic regression models were used to determine odds ratios (OR) and 95% confidence intervals (CI) for the association between HDL-C quartiles and MCI and dementia, respectively. For dementia analysis, quartiles 2–4 were collapsed due to low number of cases. Missing data was addressed through multiple imputations. There were 386 cases of MCI and 53 cases of dementia. Compared to the lowest HDL-C quartile, the highest HDL-C quartile was significantly inversely associated with MCI (OR = 0.47, 95% CI, 0.28–0.79) in the multivariable analysis. High HDL-C (quartiles 2–4) was inversely associated with dementia compared to low HDL-C (quartile 1) (OR = 0.37, 95% CI, 0.16–0.88). This study has found that high midlife HDL-C levels are inversely associated with both late-life MCI and dementia in a Japanese population.