Patients with oral cavity squamous cell carcinoma (OSCC) undergoing surgery are recommended to receive adjuvant radiation therapy with or without chemotherapy if there are unfavorable prognostic factors. A positive resection margin (PRM) and extra-capsular extension (ECE) of lymph nodes are well-known major prognostic factors. However, there is no agreement on whether oral cavity cancer patients should receive postoperative chemo-radiotherapy (CCRT) if they present with other risk factors or a combination of 2 or more risk factors. In this study, we investigated this issue and provide suggestions for adjuvant treatments.From January 2002 to December 2013, 567 OSCC patients who had undergone radical surgery were retrospectively reviewed. The 5-year loco-regional control (LRC), distant metastasis-free (DMF), disease-free survival (DFS), and overall survival (OS) were analyzed.In univariate analysis, pathological T classification, positive node, tumor depth, ECE, lymphatic or vascular or perineural invasion and histology grade are significant prognostic factors for LRC, DMF, DFS, or OS. By multivariate analysis, pathological T4 (pT4), positive node, positive surgical margin are prognostic factors for LRC. pT4, positive node and lymphatic invasion predicted for higher rate of distant metastasis. pT4, positive node, and poor differentiation tumor were prognostic factors for DFS. pT4, positive nodes, and ECE were prognostic factors for OS. These factors were used to define risk groups. We proposed PRM and ECE as major risk factors and pT4, positive nodes, close margin (≤ 5 mm, > 1 mm), tumor depth ≥ 1 cm, lymphatic invasion, vascular invasion, perineural invasion, and poor differentiation as minor risk factors. By subgroups analysis, 192 patients with at least 2 minor prognostic factors and no other major risk factors, postoperative radiotherapy (RT), or CCRT yielded significantly better 5-year LRC, DFS, and OS compared to surgery only group. For 179 patients with at least 3 minor prognostic factors and/or at least 1 major risk factor, patients receiving postoperative CCRT showed significantly better 5-year LRC, DFS, and OS compared with post-OP RT or surgery alone.Patients with 2 minor risk factors should receive postoperative RT. For patients with PRM, ECE, or >2 minor risk factors, postoperative CCRT is recommended.