Purpose: To determine if gene expression signature of invasive oral squamous cell carcinoma (OSCC) can subclassify OSCC based on survival. Experimental Design: We analyzed the expression of 131 genes in 119 OSCC, 35 normal, and 17 dysplastic mucosa to identify cluster-defined subgroups. Multivariate Cox regression was used to estimate the association between gene expression and survival. By stepwise Cox regression, the top predictive models of OSCC-specific survival were determined and compared by receiver operating characteristic analysis. Results: The 3-year overall mean ± SE survival for a cluster of 45 OSCC patients was 38.7 ± 0.09% compared with 69,1 ± 0.08% for the remaining patients. Multivariate analysis adjusted for age, sex, and stage showed that the 45 OSCC patient cluster had worse overall and OSCC- specific survival (hazard ratio, 3,31; 95% confidence interval, 1.66-6.58 and hazard ratio, 5,43; 95% confidence interval, 2.32-12.73, respectively). Stepwise Cox regression on the131 probe sets revealed that a model with a term for LAMC2 (laminin γ 2) gene expression best identified patients with worst OSCC-specific survival. We fit a Cox model with a term for a principal component analysis-derived risk score marker and two other models that combined stage with either LAMC2 or PCA. The area under the curve for models combining stage with either LAMC2 or PCA was 0,80 or 0.82, respectively, compared with 0.70 for stage alone (P = 0.013 and 0.008, respectively). Conclusions: Gene expression and stage combined predict survival of OSCC patients better than stage alone.