Purpose <p>To identify potential roles of RNA modification patterns in immunotherapy and prognosis in head and neck squamous cell carcinoma (HNSCC).</p> Methods <p>We performed a multiomics analysis of 26 “writers” from four major adenine RNA modifications in 866 HNSCC samples from 3 datasets. We identified two distinct RNA modification patterns using unsupervised clustering of 13 RNA modification writers related to prognosis, and compared biological characteristics like immune cell infiltration, stemness, TME and patient prognosis between patterns. The RNA modification score (RMscore) model was constructed to quantify the RNA modification-related subtypes of individual tumors.</p> Results <p>The RMcluster A had a longer median overall survival (OS) than RMcluster B (5.40 vs. 3.82 years, <i>p</i> = 0.017). RMcluster A had higher levels of immune cells infiltration. RMscore was an independent prognostic factor for HNSCC patients. The median OS was 5.04 years (low RMscore) vs. 2.99 years (high RMscore) (<i>p</i> = 0.012). The expression of immune cell infiltrated was significantly enhanced in patients with low RMscore. Besides, we found that RMscore was positively correlated to IC50 of many chemo or targeted therapy drugs. RMscore was validated to be correlated with the efficacy of immune checkpoints. The objective response rate (CR + PR) of immunotherapy in the low RMscore group was obviously higher than the high RMscore group (26% vs. 5%).</p> Conclusions <p>RMScore can classify RNA modification patterns and independently predict the prognosis of HNSCC patients. It might contribute to the selection of chemo or targeted drugs in HNSCC and predict the efficacy of immune checkpoints.</p>