Oropharyngeal cancer is one type of head and neck squamous cell carcinoma that is commonly associated with human papillomavirus (HPV) infection. Its incidence is increasing year by year. However, in the clinical treatment, it is found that the overall prognosis of HPV positive oropharyngeal cancer patients is better than that of HPV negative patients. But till now, the underlying mechanism that leads to this phenomenon has not been fully elucidated. This research analyzed the immune cell infiltration and function, as well as neoantigen loads between HPV positive and negative patients by bioinformatic analysis using the TCGA database, and found that the overall survival rate of HPV positive patients was significantly higher than those in the HPV negative group. Analysis of the relative abundance of immune cells in tumor tissues showed that CD8 ⁺ T cells in HPV positive patients were significantly increased compared to those in HPV negative patients, and the expression levels of effector molecules, like IFN-γ and Granzyme B, were significantly upregulated. Meanwhile, the analysis of tumor neoantigen load (TNB) showed that the TNB of HPV positive patients was lower than that of the HPV negative group. This study provides some basic theoretical support for the treating HPV-related oropharyngeal cancer.