Reoccurrence of restenosis following angioplasty of renal instent restenosis is a considerable drawback of stent-supported angioplasty of renal artery stenosis especially in small vessel diameters. We therefore prospectively studied the long-term outcome of different techniques of endovascular treatment of reoccurrence of instent renal artery restenosis after primarily successful reangioplasty focusing on the impact of covered and drug eluting stents, respectively. The study included 31 consecutive patients (33 lesions) presenting with their at least second instent restenosis following renal artery stenting who were included in a prospective follow-up program (mean follow-up 36+/-25 months, range 1-85). Primary endpoint of the study was the reoccurrence rate of instent stenosis after primarily successful treatment of instent restenosis determined by duplex ultrasound. Primary success rate was 100%, no major complication occurred. Seven lesions were treated with balloon angioplasty (21%, group 1), 7 lesions with stent-in-stent placement (21%, group 2), 6 lesions with placement of a covered stent (18%, group 3), 3 lesions with a cutting balloon (9%, group 4), and 10 lesions with placement of a drug eluting stent (31%, group 5). During follow-up, overall 12 lesions (36%) developed reoccurrence of instent restenosis: n=5 in group 1 (reoccurrence rate 71%), n=3 in group 2 (43%), n=1 in group3 (17%), 3 in group 4 (100%), and n=0 in group 5 (0%). Treatment with a cutting balloon was the only significant predictor of restenosis (hazard ratio 32.3 (95% CI, 3.3-315.0); P<0.001). Treatment of at least second renal artery instent restenosis is feasible and safe. Balloon angioplasty and the implantation of a bare metal stent, a covered stent, or a drug eluting stent seemed to offer favorable long-term patency, whereas cutting balloon angioplasty resulted in a very high rate of restenoses and should therefore be discouraged for this indication.