Objective This study aimed to evaluate the effect of mandible changes on the prognosis of oral squamous cell carcinoma (OSCC). Study Design Bone samples were collected from the mandible of 18 patients and submitted for surgical resection for OSCC treatment. Two bone fragments were removed 5 mm from the bone/tumor interface: One was submitted to microcomputed-tomography scan (19 µm) and the other to gene expression analysis by quantitative polymerase chain reaction (RANK, RANKL, OPG, and Sclerostin). A total of 8 patients presented with local, regional, or distant recurrence (unfavorable prognostic, n = 8) and 10 patients did not present with recurrence (favorable prognostic, n = 10). Kaplan-Meier estimator, log-rank test, and Cox proportional hazard regression model were performed (after determination of 2 groups of a single cut-point). Results Intracortical bone surface presented an increased risk (P = .03) of 4.6 for an unfavorable prognostic in the group with higher surface values. Also, lower bone mineral-density presented increased risk (P = .008) of 10 times and OPG lower expression presented 7.7 fold-risk (P = .07) for unfavorable prognosis. Posterior mandible tumors have lower survival rate (P = .04) compared with anterior ones. Conclusions Mandible alterations have an effect on the prognosis of patients with OSCC. Increased bone surface, lower mineral density, and lower OPG levels may have an influence for unfavorable prognosis.