Our purpose was to develop a next-generation sequencing procedure to search for NOTCH3 and HTRA1 mutations in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) features. A total of 70 patients were sequenced with semiconductor chips in an Ion Torrent Personal Genome Machine. The putative mutations were confirmed through Sanger sequencing of the corresponding patient. Six patients had a typical cysteine-involving NOTCH3 mutation. A new non-reported NOTCH3 variant (p.Pro2178Ser) was found in two patients. One patient was heterozygous for a non-reported HTRA1 variant, likely non-pathogenic (p.Ser139Ala). We found a typical NOTCH3 mutation in 9 % of the patients. None of the patients had HTRA1 variants with likely pathogenic effect. The next-generation sequencing (NGS) procedure here described would facilitate the rapid and cost-effective screening of large cohorts of CADASIL patients.