Background: With the emergence of immune checkpoint inhibitors (ICIs), there are patients with advanced cancers experiencing exceptional treatment response with overall low treatment-associated toxicities. Despite success in refractory/metastatic head and neck squamous cell carcinoma (HNSCC), only a portion of patients experience benefit from the treatment with ICIs. Critical information on predictors of patient’s response to treatment is limited. At our institution we analyzed the genomic profiles of 36 patients with advanced HNSCC who demonstrated an exceptional response to treatment with PD-1 inhibitors. Methods: We reviewed patients with histologically confirmed HNSCC that had been treated with PD-1 inhibitors at Atrium Health Wake Forest Baptist Health. Treatment regimen included pembrolizumab 200mg every 3 weeks or nivolumab 240mg every 2 weeks. Response to therapy and duration of remission were monitored via CT scans and/or MRI scans at 3-month intervals, using RECIST 1.1 criteria. Exceptional responders were defined as achieving complete response (CR) or partial response (PR) for greater than six months, or stable disease (SD) for greater than one year. Progression free survival (PFS) and overall survival (OS) were measured from the date of PD-1 inhibitor initiation. PD-L1 level was measured via FoundationOne immunohistochemistry staining and reported as combined positive score (CPS). Additionally, next generation sequencing was performed on tumor (30/36 patients) and blood (33/36 patients) specimens via FoundationOne and Guardant360 testing platforms. Results: Out of 155 HNSCC patients treated with a PD-1 inhibitor, 36 patients demonstrated an exceptional response as defined above. 20 with CR, 9 with PR and 7 with SD. With an average follow up of 32 mo (95% CI, 26 mo-ongoing), the average OS was 33 mo (95% CI, 28 mo–ongoing) and the average PFS was 25 mo (95% CI, 20 mo-ongoing). These patients underwent an average of 27 treatments (range, 10-64 treatments to date). PD-L1 average score at 36 (95% CI, 22-49) and average TMB at 19 mut/mb (range, 0-90 mut/mb). Of 290 detected gene mutations, the most frequently mutated genes were TP53 (75%), PIK3CA (42%), CDKN2A (36%), EGFR (33%), TERT (25%), BRCA2 (22%), ERBB2 (22%), HNF1A (22%), MLL2 (22%), NOTCH1 (22%), and RAD21 (22%). Conclusions: There is limited data reporting the genomic profile of exceptional responders to PD-1 inhibitors in refractory/metastatic HNSCC. Higher TMB and single gene mutations such as TP53, PIK3CA, CDKN2A, EGFR, and TERT are frequently detected in exceptional responders and may provide future direction into the investigation of predictors of response to ICIs.