Abstract Background In recent years, drug-coated balloons (DCB) have established themselves as another tool in the arsenal of interventional cardiology devices for the treatment of in-stent restenosis (ISR) lesion. Aims The study was designed to compare the biolimus DCB to the paclitaxel-coated SeQuent PleaseTM DCB. Method This was a prospective, non-inferiority, randomized, multicenter, study conducted at 20 centers in 6 countries. The primary endpoint was in-segment % diameter stenosis (%DS) at six months. The study was powered to enrol 201 patients in at 2:1 randomization to either the biolimus DCB (BCB) or the SeQuent PleaseTM DCB (SQP). Key secondary endpoints included, late-lumen loss, binary restenosis, and target lesion failure (TLF) and myocardial infarction at 1 year. Results A total of 202 patients were randomised with 135 in the BCB group and 67 in the SQP group. Mean patient age was 68.9 ± 9.9 years in the BCB group compared to 68.2 ± 10.5 years in the SQP group. At 6 months, %DS was 41.8 ± 21.3 in the BCB group compared to 31.4 ± 17.7 in the SQP group (95% confidence for the difference: 3.5-16.9, p-value for non-inferiority 0.32). At 12 months, TLF was 23.74%, in the BCB group vs 17.07% in the control group, hazard ratio (HR) of 1.44 [95% CI: 0.72-2.88], p=0.28. There were more clinically driven revascularization in the BCB group (21.61%) compared to SQP (15.61%) [HR: 1.46, 95% CI: 0.71-3.01], p=0.29. More myocardial infarction were observed in the SQP group (BCB: 7.59% vs SQP: 3.77%, [HR: 0.48, 95% CI: 0.14-1.68], p=0.24)(see Figure). Conclusions In ISR patients, the REFORM study was not able to demonstrate non-inferioirity of the biolimus DCB compared to the SeQuent Please DCB.