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OBJECTIVE: To compare acute and follow up clinical and angiographic results after treatment of in-stent restenosis (ISR) by sirolimus eluting stents (SES) with results obtained after intracoronary radiation therapy (IRT). DESIGN: Matched pair analysis. METHODS: 62 consecutive ISR lesions (< 30 mm lesion length, reference diameter < 3.5 mm) in 62 patients were treated with SES. From a database of 174 lesions (n = 141 patients) treated for ISR by intracoronary beta radiation, 62 lesions (62 patients) were pair matched with the SES group for diabetes mellitus, lesion length, vessel size, and pattern of ISR. Six month angiographic and 12 month clinical follow up results were obtained. RESULTS: Baseline clinical and angiographic characteristics were similar between the groups (not significant). SES implantation resulted in significantly lower postprocedural in-lesion diameter stenosis than did IRT (mean (SD) 14.2 (9.5)% v 21.1 (10.6)%, p = 0.001), significantly higher minimum lumen diameter at follow up (1.91 (0.58) v 1.55 (0.72) mm, p = 0.005), and a higher net gain (1.16 (0.55) v 0.77 (0.70) mm, p = 0.002). Angiographic binary in-lesion restenosis rate at six months was 11% in the SES group and 29% in the IRT group (p = 0.046). In 16 ISR lesions SES were used after failed IRT and in 46 lesions for first time ISR. In-lesion late loss was higher after use of SES for failed IRT than after use of SES for first time ISR (0.61 (0.67) mm v 0.24 (0.41) mm, p = 0.018). In a multivariate analysis prior failed IRT was the only independent predictor for recurrent restenosis after SES for ISR (p = 0.052, odds ratio 5.8). Six patients (10%) in the SES group and 17 patients (27%) in the IRT group underwent target lesion revascularisation during the 12 months of follow up (p = 0.022). CONCLUSIONS: In this non-randomised matched cohort SES achieved acute and follow up results superior to IRT for treatment of ISR even if cases of failed IRT are included. Failed IRT is a predictor of impaired SES effectiveness.