Cholesterol in brain membranes may modulate the conformational state and accumulation of alpha-synuclein in alpha-synucleinopathies.We examined the association between serum cholesterol and the risk of multiple system atrophy (MSA), one of the alpha-synucleinopathies. We enrolled 142 patients with probable MSA from two tertiary referral hospitals and 155 age- and gender-matched healthy people with no neurological disease. The levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were significantly lower in MSA patients than in controls (total cholesterol: 172.7 vs. 196.3 mg/dL, P < 0.001; LDL-C: 104.0 vs. 115.3 mg/dL, P = 0.001; HDL-C: 47.3 vs. 54.2 mg/dL, P < 0.001). After adjusting for age, gender, use of cholesterol-lowering drugs, and histories of hypertension, diabetes mellitus, and smoking, the odds ratios was 5.9 (95% CI = 2.3-11.5, P < 0.001) for MSA patients in the lowest quartile of total cholesterol and 2.6 (95% CI = 1.2-5.5, P = 0.016) for those in the lowest quartile of HDL-C, compared with the highest quartiles. Levels of serum cholesterol did not significantly correlate with disease duration or severity. Our data suggest that lower levels of total cholesterol and HDL may be associated with an increased risk of MSA.