Background: The potential for durvalumab, a PD-L1 blocking monoclonal antibody, to treat head and neck squamous cell carcinoma (HNSCC) is being evaluated in multiple clinical trials. We assessed circulating protein biomarkers in HNSCC patients prior to treatment to better understand pathways related to clinical outcomes and potentially relevant for targeting in combination with durvalumab. Methods: Sixty-six selected serum proteins were measured by multiplex immunoassay at baseline in HNSCC patients receiving durvalumab treatment: 106 patients with high PD-L1 (≥25% tumor cells; SP263 assay) in phase II HAWK trial and 52 patients with low/no PD-L1 in phase II CONDOR trial. Results: Multivariate Cox modeling demonstrated that higher baseline concentrations of angiogenic, pro-inflammatory, and myeloid-associated proteins (ANGPT2, CRP, IL6, S100A12) were associated with shorter overall survival (OS), while higher concentration of a bone formation marker and immunostimulatory hormone (BGLAP) correlated with longer OS in 158 durvalumab-treated HNSCC patients (P< 0.05). These 4 proteins also showed higher baseline levels in patients with progressive disease (PD) compared to stable disease (SD) and partial or complete responses (PR/CR), while BGLAP had lower levels in PD compared to SD or PR/CR (Mann-Whitney P< 0.05). The 5 proteins remained significantly associated with OS in a multivariate model including PD-L1, ECOG, tumor size, and neutrophil count. Bone metastasis status had no impact on the association of BGLAP with OS, which has not been reported before in HNSCC. Interestingly, ANGPT2 level above median showed the highest hazard ratio (HR = 2.2, P <0.001) among all evaluated variables. Furthermore, higher levels of VWF, an angiogenesis-related protein, correlated with shorter OS by univariate survival analysis (P < 0.001). Conclusions: Our results suggested an important role of angiogenesis in the resistance of HNSCC patients to durvalumab treatment, and ANGPT2 may have predictive utility for durvalumab combination with an anti-angiogenic agent. The predictive value of BGLAP remains to be evaluated in a randomized clinical study. Clinical trial information: NCT02207530; NCT02319044