Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3 gene mutations affecting cysteine residues in the Notch3 receptor's extracellular domain. The disease is characterized by recurrent strokes, cognitive decline, migraines with aura, epilepsy, gait disturbances, and psychiatric problems. This study investigated the clinical features and NOTCH3 mutations in Cypriot CADASIL patients to identify genotype-phenotype correlations. Nineteen genetically confirmed CADASIL patients (10 males, 9 females) were studied, 18 symptomatic and one asymptomatic 24-year-old son of a patient. Phenotypical and genotypical data were analysed retrospectively. Haplotype analysis was performed in 10 consented p.Arg449Cys patients by using six microsatellite markers flanking the NOTCH3 gene, using PHASE software v2.1.1. The NOTCH3 c.1345C>T, p.Arg449Cys mutation was found in 84% of cases (16/19), while the remaining 16% exhibited other mutations. Symptomatic patients with this mutation had a mean onset age of 47 years. Ischemic stroke (69%) and cognitive impairment (69%) were the most prevalent clinical manifestations found in these patients, while epilepsy was less common (19%). All symptomatic p.Arg449Cys patients showed white matter hyperintensities in MRI. Families carrying p.Arg449Cys shared a common haplotype at D19S411 (p.Arg607Cys-16) with >0.6 probability. The carriers originate from seven different villages, six of which are in a mountain region. We have demonstrated a unique clinical phenotype in Cypriot patients attributable to a specific NOTCH3 genotype. Additionally, a common haplotype was identified among p.Arg449Cys patients. Our findings illustrate clinical variability and genetic diversity in CADASIL patients, suggesting a potential founder effect.