Percutaneous intervention of coronary chronic total occlusion (CTO) from in-stent restenosis (ISR) is hindered by difficulty to cross the lesion with conventional guidewires. This study describes the successful treatment of five cases of CTOs from ISR using the Frontrunner controlled blunt microdissection catheter. Four of the five cases had failed previous attempts of percutaneous intervention with conventional guidewires. The Frontrunner catheter successfully facilitated the placement of guidewire into the distal true lumen in all five cases. The median crossing time was 10 min. No subintimal delivery of guidewire or vascular perforation was observed. TIMI 3 flow was achieved in all target vessels after further balloon angioplasty or stenting. The Frontrunner device is a safe and effective tool in the treatment of CTOs from ISR.