There is limited data on the efficacy of paclitaxel-coated balloon (PCB) compared to stents for de novo coronary lesions. The purpose of this study was to compare the efficacy of PCB treatment with stent implantation for de novo coronary lesions after successful plain old balloon angioplasty (POBA) guided by fractional flow reserve (FFR). In 200 patients scheduled for elective percutaneous coronary intervention (PCI) for de novo lesions, FFR was measured after POBA (POBA–FFR). If POBA–FFR was ≥ 0.75, patients were treated with PCB (PCB group, n = 78) or stent (Stent group, n = 73). If POBA–FFR was < 0.75, stent was implanted as planned (Reference group, n = 42). The primary endpoint was late lumen loss at 9 months and the secondary endpoint was adverse cardiac events (cardiac death, myocardial infarction, target lesion thrombosis, or repeat revascularization) at 12 months follow-up. There was no between-group differences in the POBA–FFR (0.87 ± 0.05 in PCB, 0.89 ± 0.06 in stent, p = 0.101). At 9 months, late lumen loss was significantly lower in the PCB group compared to the Stent group (0.05 ± 0.33 vs. 0.59 ± 0.76 mm, p < 0.001). Adverse cardiac events were not different between the PCB, Stent and Reference groups (2.6, 5.5, and 9.5% respectively; p = 0.430 for PCB vs. Stent group; p = 0.229 for the reference vs. both other groups). PCB treatment guided by POBA–FFR showed excellent 9 months angiographic and functional results, as well as comparable 12 months clinical outcomes, compared with stent implantation for de novo coronary lesions.