Programmed cell death protein‐1 (PD-1) targeted immunotherapy is approved for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treatment. Although its efficacy correlates with PD-L1 expression, response is limited even among positive cases. We employed digital spatial profiling (DSP) to discover potential biomarkers of immunotherapy outcomes in HNSCC. Fifty prospectively collected, pre-treatment biopsy samples from anti-PD-1-treated R/M HNSCC patients, were assessed using DSP, for 71 proteins in 4 molecularly defined compartments (tumor, leukocyte, macrophage and stroma). Markers were evaluated for associations with progression free (PFS) and overall survival (OS). High beta-2 microglobulin (B2M), LAG-3, CD25 and 4-1BB in tumor; high B2M, CD45, CD4 in stroma, and low fibronectin in the macrophage compartment, correlated with prolonged PFS. Improved PFS and OS were observed for cases with high B2M by quantitative and mRNA. Findings were validated in an independent cohort for PFS [HR, 0.41; 95% CI, 0.19-0.93; p = 0.034]. B2M-high tumors showed enrichment with immune-cell and immune-checkpoint markers. Our study illustrates B2M expression is associated with improved survival for ICI-treated HNSCC.