The purpose of this retrospective study was to develop a pre-treatment laboratory prognostic index (LPI) based on laboratory results that might serve as an extension to clinicopathological parameters for prognosis and treatment in patients with oral squamous cell carcinoma (OSCC). Pre-treatment LPI was calculated from C-reactive protein (CRP), hemoglobin (Hb) levels, and count of white blood cells (WBCs) due to significant (P < 0.05) association with locoregional recurrence measured for each parameter by receiver operating characteristic (ROC) curves in 187 patients with OSCC. Positive predictive values (+PV, precision rate) and negative predictive values (-PV) of LPI were measured. Likelihood ratios (LRs) were used to assess how good the pre-treatment LPI diagnostic test is to determine locoregional recurrence of the disease. CRP expression by cancer cells was confirmed by immunocytochemistry and FACS analysis. ROC analysis determined cutoff values for CRP levels, Hb levels, and WBC count and showed significant differences between nonrecurrent and recurrent group of OSCC. On univariate analysis, patients with high pre-treatment LPI (LPI ≥ 2, hazard ratio (HR) = 3.8670, 95% confidence interval (CI) = 2.2518-6.6407, P < 0.0001) had a significant poorer prognosis. Multivariate analysis showed that the most important independent prognostic factor was high pre-treatment LPI (LPI ≥ 2, HR = 3.6450, 95% CI = 2.3964-5.5441, P < 0.0001). Moreover, pre-treatment LPI ≥ 2 showed high probability that locoregional recurrence will be present later (+PV, LPI ≥ 2, 86.4%, 95% CI = 65.1-97.1). High +LR gave an excellent indication for a good quality of the test (LR+, LPI ≥ 2, 12.77, 95% CI = 8.8-18.6). Immunohistochemistry and FACS analysis confirmed inflammatory CRP expression by cancer cells. This study highlights the combination of inflammatory CRP levels, Hb levels, and WBC count as the most important independent prognostic factor in predicting disease recurrence of patients with OSCC. LPI can be used as a pre-treatment inflammatory biomarker that may identify OSCC with a more aggressive biological phenotype of the disease and might be helpful for guiding further post-operative treatment in OSCC.