Cerebral small-vessel disease, a common disorder in the aged, causes dementia and disability of motor function. The molecular pathology of the disorder remains to be elucidated. Missense and nonsense mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), a hereditary cerebral small-vessel disease. HTRA1 represses transforming growth factor-β (TGF-β) signaling by its protease activity. CARASIL-associated mutant HTRA1s have decreased protease activity and fail to repress the TGF-β signaling, raising the possibility that chronic upregulation in the signaling pathways are involved in the pathogenesis of CARASIL. Here we show that increased expression of LAP and ED-A fibronectin are limited to affected small arteries in patients with CARASIL. We also demonstrate that HTRA1 cleaves the pro-domain of proTGF-β1 in the endoplasmic reticulum proceeding with processing by furin in trans Golgi network and reduces the amount of secreted TGF-β1 and CARASIL-associated mutant HTRA1s cannot. These results indicate that HtrA1 suppresses TGF-β signaling by aberrant processing of proTGF-β and the dysregulation of the signaling caused by mutated HTRA1s is involved in the pathogensis of CARASIL.