Most patients with relapsed or metastatic head and neck squamous cell carcinoma (rmHNSCC) do not experience durable responses to PD-1 immune checkpoint inhibitors. PD-L1 tissue expression is the most commonly assessed response marker, but an insufficient predictor of treatment outcome. To identify suitable response biomarkers, we profiled the FOCUS trial (Registered at ClinicalTrials.gov: NCT05075122) cohort for several blood- and tissue-based markers. PD-L1 levels in the tumor or tumor microenvironment were not associated with treatment benefit. In contrast, inflammation-related markers such as IL-6, sCD25, and sTIM-3, as well as high peripheral neutrophils, cell-free DNA levels, and T cell receptor repertoire clonality, were associated with poor clinical outcomes. Patients lacking these high-risk markers performed remarkably well on inhibition of immune checkpoints with pembrolizumab. Biomarker-guided patient selection for pembrolizumab monotherapy or novel combinatorial approaches-potentially including anti-inflammatory agents-for patients with immune-impaired, inflammatory profiles may be the next step in personalizing immunotherapy for these hard-to-treat patients.