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Backgrounds:The main aim of the present report is to identify the factors most strongly related to the development of distant metastasis in patients affected by oral squamous cell carcinoma (OSCC), and to define a protocol for the early detection of distant metastasis.Methods: Clinical records of 297 patients with OSCC treated with surgery ± adjuvant treatment were retrospectively analyzed. Patients were divided into two groups: (I) patients with distant metastasis and (II) patients without distant metastasis. The relationship between several histopathological factors and the risk of developing distant metastasis was analyzed.Results: Lung was the most affected organ by distant metastasis of OSCC. T3 and T4 stage, N2 and N3 stage, tumor thickness >1 cm, perineural invasion, extracapsular spread, cervical and locoregional recurrence, clinical or pathological stage IV and involvement of contralateral neck were strongly associated with the development of distant metastasis. In addition, the possibility of developing distant metastases is more than 4 times greater when two or more of these risk factors are present.Conclusions: Performing a chest computed tomography (CT) scan or positron emission tomography (PET) CT before surgery in patient with two or more risk factors would be useful for identifying patients with early distant dissemination. Due to the high prevalence of lung metastasis, a chest scan would be sufficient to detect most of these cases.