Objective The study was designed to investigate if vascular occlusion in the internal carotid artery (ICA) or the contralateral vertebral artery (VA) contribute to developing in-stent restenosis (ISR) in patients with vertebral artery ostium stenosis (VAOS). Methods 420 consecutive patients treated with VAOS stents (from a population of 8145 patients with VAOS) from January 2013 to December 2014 were analyzed in this retrospective study; 216 with drug eluted stents and 204 with bare metal stents. Based on pre-stent DSA findings, patients were divided into four groups: both carotid and vertebral arteries patent (PAT), ICA occlusion (ICA-OCC), contralateral VA occlusion (CVA-OCC), and combined occlusions (C-OCC). The incidence of ISR (stenosis > 50%) was compared between groups using Cox regression analysis. Results Of the 420 patients, the mean incidence of ISR was 36.4%, with a median 12 months of follow-up (IQR 3-12). Logistic regression analysis showed that drug eluting stent had less ISR than bare metal stent (OR=0.38, 95% CI 0.19 to 0.75, P=0.01). Cox regression analysis showed that CVA-OCC (HR=1.63, P=0.02) and C-OCC (HR=3.30, P=0.001) were risk factors for ISR but not ICA-OCC (P=0.31). In the CVA-OCC and C-OCC groups, in-stent peak systolic velocity (PSV) =140 cm/s, 1 day after successful stenting, was associated with subsequent development of ISR (OR=2.81, 95% CI 1.06 to 7.43, P=0.04). Conclusion C ontralateral VA occlusion at the time of stenting increased the risk of ISR, especially if stent PSV on day 1 was > 140 cm/s. Bare metal stents had more ISR than drug eluting stents.