Little has been reported on whether abnormal lipid metabolism affects hydrocephalus, although congenital malformations and infectious diseases are major causal factors for hydrocephalus development. In a study on the pathogenesis of atherogenesis in mice, we unexpectedly discovered that hydrocephalus occurred in partial apolipoptotein E (apoE) and low-density lipoprotein receptor (LDLR) double-knockout (apoE−/−/LDLR−/−) mice fed either chow or a high-fat and high-cholesterol diet between the ages of 4 and 12 weeks. In the 12-week-old high-fat and high-cholesterol group, the incidence rate was as high as 15%. Transcription levels of transforming growth factor-β1 (TGF-β1), Smad3, Smad4, and Smad7 in the cortex of the hydrocephalic cerebrum were significant downregulated in 4-week-old mice, but were increased in the 8 and 12-week-old groups compared with that of age-matched nonhydrocephalic mice. The mRNA level of tissue inhibitor of metalloproteinases 1 was significantly increased, whereas matrix metalloproteinase-9 was lower in hydrocephalic mice of all ages. The translation level of TGF-β1 increased in the hydrocephalic brains of 8 and 12-week-old mice. This study provides primary evidence for the connection between lipid metabolic disorder and hydrocephalus development. This may suggest that both hyperglyceridemia and hypercholesterolemia are harmful factors in hydrocephalus development because of adverse effects on TGF-β1/Smad signaling in the brain.