Randomized clinical trials investigating the treatment of coronary in-stent restenosis with paclitaxel iopromide coated balloon catheters have shown favorable results. The aim of the present clinical investigation was to assess the efficacy of a novel paclitaxel urea coated angioplasty balloon in the treatment of coronary in-stent restenosis. A total of 26 restenotic bare metal stents in 23 patients with a lesion length of 22.8 ± 11.1 mm and a reference vessel diameter of 2.64 ± 0.31 mm were treated. Up to six months and including the six-month angiographic control, only one target lesion revascularization was necessary; in total, the rate of major adverse cardiovascular events until six-month follow-up was 4.3 %. In-stent late lumen loss was 0.07 ± 0.37 mm, in-segment late lumen loss 0.02 ± 0.50 mm. Binary restenosis was present in one patient (4.3%). The results of this first-in-human series with a paclitaxel urea coated balloon are comparable to paclitaxel iopromide coated balloon catheters. Randomized, controlled clinical trials are warranted to further evaluate this promising approach.