Low high-density lipoprotein cholesterol is associated with an increased risk for cardiovascular disease and stroke. At the same time, cardiovascular disease and stroke are important risk factors for dementia. We assessed the association between total and fractionated cholesterol and cognitive impairment and explored whether observed associations were dependent on or independent of atherosclerotic disease. In a population-based study, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were measured in 561 subjects 85 years old and grouped in three equal strata representing decreasing serum concentrations. History of cardiovascular disease and stroke was determined. All subjects completed the Mini-Mental State Examination (MMSE), and the presence of dementia was determined. Median MMSE scores were significantly lower in subjects with low high-density lipoprotein cholesterol (25 points vs 27 points, p < 0.001). No differences in MMSE scores were found for other lipids and lipoproteins. MMSE scores in subjects with and without cardiovascular disease were 26 and 27 points (p = 0.007), respectively, and in subjects with and without stroke were 21 and 26 points (p < 0.001), respectively. The associations between low MMSE scores and low high-density lipoprotein cholesterol remained significant after subjects with cardiovascular disease or stroke were excluded. In a comparison of subjects with low high-density lipoprotein cholesterol with subjects with high high-density lipoprotein cholesterol, the odds ratio for dementia was 2.3 (95% confidence interval, 1.2-4.3), and in subjects without cardiovascular disease or stroke, it was 3.7 (95% confidence interval, 1.3-10.1). All odds ratios were unaffected by education, low-density lipoprotein cholesterol, triglycerides, and survival. Low high-density lipoprotein cholesterol is associated with cognitive impairment and dementia. At least part of the association between high-density lipoprotein cholesterol and cognitive function is independent of atherosclerotic disease.