A number of genetic variants were suggested to be associated with oral malignancy, few variants can be replicated. The aim of this study was to identify significant variants that enhanced personal risk prediction for oral malignancy. A total of 360 patients diagnosed with oral squamous cell carcinoma, 486 controls and 17 newly diagnosed patients with OPMD including leukoplakia or oral submucous fibrosis were recruited. Fifteen tagSNPs which were derived from somatic mutations were genotyped and examined in associations with the occurrence of oral malignancy. Environmental variables along with the SNPs data were used to developed risk predictive models for oral malignancy occurrence. The stepwise model analysis was conducted to fit the best model in an economically efficient way. Two tagSNPs, rs28647489 in FAT1 gene and rs550675 in COL9A1 gene, were significantly associated with the risk of oral malignancy. The sensitivity and specificity were 85.7% and 85.5%, respectively (area under the receiver operating characteristic curve (AUC) was 0.91) for predicting oral squamous cell carcinoma occurrence with the combined genetic variants, betel-quid, alcohol and age. The AUC for OPMD was only 0.69. The predictive probability of squamous cell carcinoma occurrence for genetic risk score without substance use increased from 10% up to 43%; with substance use increased from 73% up to 92%. Genetic variants with or without substance use may enhance risk prediction for oral malignancy occurrence in male population. The prediction model may be useful as a clinical index for oral malignancy occurrence and its risk assessments.