Abstract: The present disclosure describes methods and compositions for diagnosing or predicting likelihood of a OSCC recurrence in a subject having undergone OSCC resection comprising: a) determining an expression level of one or more biomarkers selected from Table 4, 5 and/or 7, optionally MMP1, COL4A1, THBS2 and/or P4HA2 in a test sample from the subject, the one or more biomarkers comprising at least one of THBS2 and P4HA2, and b) comparing the expression level of the one or more biomarkers with a control, wherein a difference or a similarity in the expression level of the one or more biomarkers between the test sample and the control is used to diagnose or predict the likelihood of OSCC recurrence in the subject In particular, the present disclosure describes methods and compositions using a four-gene biomarker signature that can predict recurrence of oral squamous cell carcinoma in subjects that have histologically normal surgical resection margins.