OBJECTIVE : The presence of cancer stem-like cells (CSCs) in the majority of tumors is one of the factors responsible for disease relapse in oral squamous cell carcinoma (OSCC). In this study, we investigated the role of octamer-binding transcription factor 4 (OCT4) and Kruppel-like factor 4 (KLF4) in OSCC progression and disease relapse. METHODS : In this study, 102 patients with OSCC were included. The expression of β-catenin and CSC markers (KLF4 and OCT4) in surgical cut margin and tumor were investigated through Western blot analysis, immunohistochemistry, and quantitative polymerase chain reaction analysis. The χ2 test was used to evaluate the association of β-catenin, OCT4, and KLF4 expression with clinicopathologic characteristics. Kaplan-Meier and Cox regression analyses were performed to correlate different clinical factors with the prognoses of patients with OSCC. RESULTS : We observed increased expression of OCT4, KLF4, and β-catenin in the cut margins (CMs) in recurrent OSCC. The χ2 test exhibited recurrence as one of the key factors associated with high expression of these markers. Kaplan-Meier and COX regression analyses demonstrated that increased expression of KLF4 in the CM region of recurrent patients was independently associated with a poor prognosis. CONCLUSIONS : Our findings indicated that expression of KLF4 can be used for monitoring disease progression and may serve as prognostic marker to predict recurrence.