Oral squamous cell carcinoma (OSCC) with invasion into the mandibular medullary space has been reported to be a predictive factor for cervical lymph node metastasis (CLNM). As CLNM has been associated with the stemness of cancer cells, we aimed to evaluate the relationship between clinical characteristics and immunohistochemical findings on the invasion front of the medullary invasive OSCC and CLNM. The medical records of 25 patients with the mandibular medullary invasive OSCC who were performed mandibulectomy and neck dissection in our department from 2010 to 2016 were examined. Serial sections were stained with antibodies against CD44 variant 6 (CD44v6) to examine cancer stemness and to evaluate the number of tumor buds in the medullary invasion front of the mandibular invasive OSCC. Categorical data were analyzed by Fisher’s exact test. The expression of CD44v6 and the number of tumor buds between the groups with and without pathological CLNM (CLNM+ and CLNM-, respectively) were analyzed using the Mann-Whitney U test. Of the 25 patients, 11 patients were CLNM+. Of the several measured variables, histologic differentiation of the mandibular invasive OSCC was a significant factor for CLNM+. CD44v6 expression and tumor bud formation in the medullary invasion front of the mandibular invasive OSCC were significantly higher in the CLNM+ group, suggests that both CD44v6 and tumor budding in the medullary invasion front are predictive factors for CLNM.