Aims: Recently, drug-eluting stents (DESs) have been widely adopted for patients on chronic hemodialysis (HD). However, whether DES implantation is associated with a reduced rate of in-stent restenosis (ISR) is unclear. We investigated the incidence of ISR and its predictors in patients on HD after DES implantation. Methods and Results: We analyzed 194 consecutive patients (331 lesions) on HD who underwent follow-up angiography after DES implantation. ISR was observed in 74 lesions (22.4%). Angiographically, the relative incidence of AHA/ACC type C lesion was increased (47 vs. 32%; p = 0.043), the minimal lumen diameter (MLD) before DES implantation was smaller (0.82 ± 0.49 vs. 0.97 ± 0.45 mm; p < 0.01), and the lesion length (LL) was increased (30.2 ± 16.1 vs. 24.4 ± 12.1 mm; p = 0.023) in lesions with ISR compared to those without ISR. The rate of rotational atherectomy use was also increased in lesions with ISR compared to those without ISR (50% vs. 25%; p < 0.01). In a multivariate analysis, the MLD before DES implantation (odds ratio [OR] = 0.50, 95% confidence interval [CI] 0.27–0.91, p = 0.024), LL (OR = 1.02, 95% CI 1.00–1.04, p = 0.030) and the use of rotational atherectomy (OR = 2.71, 95% CI 1.55–4.72, p < 0.01) were independent predictors of ISR. The incidence of ISR was similar between lesions treated with the first-generation (25.8%) and the second-generation DESs (20.4%). Conclusions: ISR was observed in 74 lesions (22.4%). A small MLD, long LL, and the use of rotational atherectomy were independent predictors of ISR after DES implantation in patients on HD. There was no significant difference in the ISR rate between the first- and the second-generation DESs.