Summary Early local recurrence is one of the main causes of treatment failure after definitive therapy of oral squamous cell carcinoma (OSCC), contributing significantly for the relative low survival rates of this neoplasia. The aim of this study was to investigate the clinical, histological and molecular factors involved in early local recurrence of OSCC, which may lead to better risk assessment in some specific cases. Twenty-seven patients with early recurrent OSCC were matched with 54 patients with the same clinical stage and tumor site but without local recurrence, in a pair-matched study design. All cases were evaluated in relation to the clinicopathological features and immunohistochemical expression of Ki-67, p53, bcl-2, FAS, Erb-B2, β-catenin, and E-cadherin. The variables associated with ELR were alcohol consumption ( p = 0.019), treatment performed ( p = 0.041), and expression of Ki-67 ( p = 0.028), FAS ( p = 0.005) and membrane β-catenin ( p = 0.026). The multivariate survival analysis (Cox regression) showed that surgery with adjuvant radiotherapy [OR = 0.26 (95% CI, 0.1–0.6)] and FAS expression [OR = 0.21 (95% CI, 0.1–0.5)] had a significant effect for ELR development. Radiotherapy had no significant impact on patients’ overall survival. Therefore, both treatment and molecular characteristics of the tumor seem to be involved in early local recurrence.