SCN1A variants cause a range of epilepsy syndromes, including Dravet syndrome, leading to early cognitive and functional impairment. Despite advances in medical management, drug-resistant epilepsy remains common. Vagal nerve stimulation (VNS) has been suggested reducing seizure frequency in these patients but there is a lack of long-term follow-up, quantitative analysis that corrected for confounding factors such as antiseizure medications (ASMs) and the impact of VNS settings on response. This two-center, retrospective cohort study analyzed 12-month and for the first time up to ten-year seizure outcomes in therapy-refractory epilepsy patients with loss-of-function SCN1A variants (93.75% Dravet Syndrome) who underwent VNS implantation. A ≥50% seizure frequency reduction was observed in 93.75% (15/16) of patients in the 12-month and 87.5% (14/15) in the ten-year period. Median seizure frequency was significantly lower in both follow-up periods than in the pre-implantation period. Linear mixed-effects regression showed that the reduction in seizure burden was independent of ASM use, and the VNS duty cycle was significantly associated with seizure reduction. Three individuals (18.8%) experienced minor side effects. Our results highlight the benefits of genotype-driven therapeutic interventions such as VNS in patients with SCN1A -related epilepsy. This study emphasizes the need for further implementation of genotype-driven clinical decision-making.