Drug-Coated Balloons (DCB) have been widely used in interventional treatment for coronary artery de novo lesions. However, DCB treatment still have a certain proportion of target vessel restenosis (TLR) and adverse follow-up events. Quantitative flow ratio (QFR) loss are important indicators for evaluating long-term vascular functional changes. However, in patients with de novo lesions treated by DCB, the potential risk and protective factors affecting QFR loss remain unclear. The aim of this study was to explore the factors affecting QFR loss in patients with de novo lesion after DCB-angioplasty. Patients who underwent DCB-only intervention de novo lesions and underwent coronary angiography within 12 ± 3 months were enrolled. The QFR loss was defined as difference between the immediate post-procedure QFR and follow-up QFR. The subjects were divided into high QFR loss and low QFR loss groups according to the binary method. The predictors of QFR loss were then analyzed. A total of 115 patients with 1-year follow-up were included in this study, and the median follow-up time was 357 days. Multivariate Logistic analysis showed that patients with diabetes mellitus (OR = 4.937, 95%CI 1.497-16.278, P = 0.009) and LDL-C > 1.8 mmol/L (OR = 2.575, 95%CI 1.021-6.493, P = 0.045) was significantly associated with higher QFR loss 1 year after surgery. In patients undergoing DCB treatment for coronary de novo lesions, diabetes is an independent risk factor for late QFR loss at 1 year. Conversely, achieving LDL-C targets during follow-up is an independent protective factor against late QFR loss at 1 year.