Introduction: Optimal management of severe carotid in-stent restenosis remains unknown. Prevalence and risk factors of first and recurrent carotid in-stent restenosis in the multi-stent approach have not been established yet. Aim: To evaluate the safety of different methods of endovascular treatment of carotid in-stent restenosis/recurrent restenosis and to establish its rate and risk factors. Material and methods: Between January 2001 and June 2016, 2637 neuroprotected carotid artery stenting (CAS) procedures were performed in 2443 patients (men: 67.0%; mean age: 67.9 ±8.8 years, symptomatic: 45.5%). Doppler ultrasound (DUS) evaluation was performed at discharge, after 3-6 months, 12 months, and then annually. Peak systolic velocity of 2-3 and > 3.0 m/s as well as end diastolic velocity of 0.5-0.9 and > 0.9 m/s were DUS criteria for 50-69% and ≥ 70% carotid in-stent restenosis (ISR) respectively. For angiographically confirmed ≥ 70% stenosis balloon re-angioplasty was first line treatment. Results: Out of 95 DUS detected > 50% ISR (95/2637; 3.6%), 53 were confirmed in angiography as ≥ 70% (53/2637; 2.0%, one total occlusion). All patients were treated with bare balloon (n = 19), drug-eluting balloon (n = 27) or stent-supported (n = 6) angioplasty. One procedure was complicated with stroke (1.9%). Angiographic diameter stenosis (DS) was reduced from 83 ±8.3% to 13 ±7.6% (p < 0.001). There were 13 cases of ≥ 70% recurrent ISR. Bilateral and high-grade stenosis were independent risk factors of restenosis. Initial Carotid Wallstent implantation was a risk factor of first and recurrent in-stent restenosis. Conclusions: Endovascular treatment of carotid in-stent restenosis is safe. Bilateral and high-grade carotid artery stenosis may increase the risk of restenosis. Initial Carotid Wallstent implantation may increase the risk of first and recurrent restenosis.