This study seeks to analyze the factors associated with the occurrence of squamous cell carcinoma in oral non-healing ulcers for more than 3 weeks and investigate the role of endoscopy with narrow-band imaging system (NBI) in detecting carcinoma in these lesions. The demographic and clinicopathological data of patients receiving surgical interventions for chronic oral non-healing ulcers, and the intraepithelial papillary capillary loop patterns shown by NBI were retrospectively reviewed and analyzed. A total of 63 patients (41 males and 22 females) with mean age of 57.9 ± 16.7 years were enrolled. In univariate analysis, ulcers with induration, history of oral cancer, and intraepithelial microvasculature of NBI were factors associated with the occurrence of squamous cell carcinoma in oral non-healing ulcers. Multivariate analysis showed that the intraepithelial microvasculature of NBI was the only independent factor predicting the occurrence of carcinoma in oral chronic non-healing ulcers with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 93.75 %, 91.49 %, 78.95 %, 97.73 %, and 92.06 %, respectively. Morphology of intraepithelial microvasculature of NBI, or twisted, elongated, and destructive pattern of intraepithelial papillary capillary loop, is the only independent factor associated with the occurrence of squamous cell carcinoma in oral chronic non-healing ulcers. Endoscope with NBI is a rapid, safe, and promising tool in detecting squamous cell carcinoma in oral chronic non-healing ulcers.