Background. The advent of drug-eluting balloons (DEBs) is a promising development for coronary revascularization procedures, especially for in-stent restenosis (ISR). This study aims to highlight our experience with DEBs in the treatment of drug-eluting ISR at a tertiary care hospital in Pakistan. Methods. All patients presenting to our institution from August 2008 to February 2011 with significant drug-eluting in-stent restenosis (DES-ISR) who were eligible to receive treatment via DEB were included in the analysis. Patient baseline characteristics and angiographic data about the lesion characteristics were obtained. Postprocedural and follow-up endpoints, including cardiac death, myocardial infarction, and repeat revascularization, ie, major adverse cardiovascular events (MACE), were included in the analysis. Results. A total of 26 patients received treatment with DEB in the study period, with a significant number having major predisposing factors for the development of ischemic heart disease (IHD; 46% diabetics; 92% hypertensives). The culprit lesion was most commonly identified in the left anterior descending (31%), with presence of American College of Cardiology/American Heart Association lesion type C in 68% of patients. The SeQuent Please paclitaxel-eluting balloon (B. Braun) was used for revascularization. Patients were followed for a median of 16 months. Only 5 patients (19%) developed MACE during this period. Conclusion. Our experience demonstrates the effectiveness of DEBs in the treatment of drug-eluting ISR, especially in complex lesions with patients having significant risk factors for development of IHD. However, further studies are needed to define their indications in this role.