Objective Small coronary vessel disease (disease affecting coronary vessels with main branch diameters of <= 2.75 mm) is a common and intractable problem in percutaneous coronary intervention (PCI). This study was designed to test the theory that the effectiveness and safety of drug-eluting balloons for the treatment of de novo lesions in small coronary vessels are non-inferior to those of drug-eluting stents. Methods We designed a prospective, multicenter, randomized, controlled clinical trial aiming to assess the effectiveness and safety of the RESTORE (Cardionovum, Bonn, Germany) drug-eluting balloon (DEB) versus the RESOLUTE (R) (Medtronic, USA) drug-eluting stent (DES) in the treatment of small coronary vessel disease. This trial started in August 2016. A total of 230 patients with a reference vessel diameter (RVD) >= 2.25 mm and <= 2.75 mm were randomly assigned to treatment with a DEB or a DES at a 1:1 ratio. The study was also designed to enroll 30 patients with an RVD >= 2.00 mm and <= 2.25 mm in the tiny vessel cohort. Results The key baseline data include demographic characteristics, relative medical history, baseline angiographic values and baseline procedural characteristics. The primary endpoint is in-segment diameter stenosis at nine months after the index procedure. Secondary endpoints include acute success, all-cause death, myocardial infarction, target vessel revascularization, target lesion revascularization and stent thrombosis. Conclusions The study will evaluate the clinical efficacy, angiographic outcomes, and safety of DEBs compared to DESs in the treatment of de novo coronary artery lesions in small vessels.