Abstract Background: DNA damage repair (DDR) pathway have been reported in several cancer, and known as a predictive biomarker of platinum-based chemotherapy, PARP inhibitor therapy, radiotherapy, and immunotherapy. However, the predictive value and mutated characteristics of DDR in patients with head and neck cancer (HNC) is still uncertain. The purpose of this study is to assess the frequency of DDR mutations, and the correlation between DDR mutations and immunogenic biomarker such as tumor mutation burden (TMB), microsatellite instability (MSI) and PD-L1 expression in Chinese HNC patients. Methods: Genomic profiling of DNA was performed through a next-generation sequencing (NGS) (panel on 381/733-gene) on tissue from Chinese patients with head and neck cancer between January 23, 2017 and April 10 2020. TMB was defined as total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was determined by immunohistochemistry staining using Dako 22C3. Germline or somatic mutations of 35 DDR genes were classified as DDR gene mutations. Result: Genetic mutation of 319 HNC patients were analyzed using NGS, of which 32 (10.03%) harbored alterations in DDR genes. The most frequently mutated DDR genes were BRCA2 (3.23%), followed by FANCA (2.02%), BRCA1 (1.61%), RAD51 (0.81%), RAD50 (0.81%), PMS2 (0.81%), and PLAB2 (0.81%). The frequency of KMT2C, CD274, FBXW7, APC, NOTCH1, PDCD1LG2, RB1, LRP1B, and JAK2 mutations was higher in DDR mutations (DDRmut) than in DDR wild-type (DDRwt) patients. PD-L1 status analysis was performed in 265 HNC patients, including 24 DDRmut patients and 241 DDRwt patients. But there was no significant difference on PD-L1 expression between DDRmut t and DDRwt (P=0.93). 310 HNC patients (including 31 DDRmut patients and 279 DDRwt patients) could be evaluated for TMB, the results showed that DDRmut (10.13Muts/Mb) was associated with higher TMB than DDRwt (5.65Muts/Mb) (P = 0.0031). Of the 308 HNC patients (including 31 DDRmut patients and 277 DDRwt), only 3 (0.97%) were diagnosed as MSI-H, including 2 (6.45%) patients with DDRmut and 1 (0.36%) patient with DDRwt. Conclusions: The DDR pathway genes alteration characteristics was presented in Chinese HNC patients, and was associated with a higher TMB level. These findings provide a theoretical basis for future investigation of clinical therapy in DDR mutated Chinese HNC patients. Citation Format: Yong Chen, Yan Wang, Yating Zheng, Wenzhuan Xie, Mengli Huang. Investigation of DNA damage repair mutated characteristics and correlation with immunogenic biomarker in Chinese head and neck cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2206.