Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease characterized by different molecular subgroups and clinical features. Therefore, it is important to uncover reliable molecular biomarkers for distinguishing different risk patient subgroup. Here, we conducted a multi-omics analysis to examine the joint predictive power of a multi-type RNA signature in the prognosis of HNSCC patients through integration analysis of mRNA, miRNA, and lncRNA expression profiles and clinical data in a large number of HNSCC patients. A multi-type RNA signature (15SigRS) was constructed which can classify patients into the high-risk group and low-risk group with the significantly different outcome [hazard ratio (HR) = 2.718, 95% confidence interval (CI), 2.258-3.272, p < 0.001] in the discovery data set, and subsequently validated in the Cancer Genome Atlas (TCGA) testing data set (HR = 1.299, 95% CI, 1.170-1.442, p < 0.001) and another independent GSE65858 data set (HR = 1.077, 95% CI, 1.016-1.143, p = 0.013). Further multivariate Cox regression analysis and stratification analysis demonstrated the independence of predictive performance of the 15SigRS relative to conventional clinicopathological factors. Furthermore, the 15SigRS has a prior performance in prognostic prediction than other single RNA type-based signatures. Functional analysis suggested that the 15SigRS are involved in immune-or metabolism-related KEGG pathways. In summary, our study demonstrated the potential application of mixed RNA types as molecular markers for predicting the outcome of cancer patients.