To evaluate the prognostic values of different protein expression in the progression of squamous cell carcinoma of the head and neck (SCCHN) patients, we conducted immunohistochemical (IHC) analysis in tissue samples of different patients enrolled on SWOG protocol S0420. S0420 was a phase II trial to evaluate the efficacy and safety of single-agent sorafenib in chemotherapy-naïve patients with metastatic or recurrent SCCHN. The primary end point was response probability, i.e., confirmed complete (CR) and partial response (PR). Sorafenib was administered orally at 400 mg twice daily on a continuous basis in 28-day cycles to eligible patients. Responses were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. IHC analysis was performed for various markers and data were analyzed statistically. IHC data were obtained from 19 patients enrolled on S0420. There was a high frequency of cases with expression of the angiogenesis markers SMA, HIF-1α, Raf-1, VEGF and VEGF-R. None of the markers were significantly associated with response. Negative HER-2 status was associated with longer progression-free survival (PFS), P=0.04. Negative NRP-1 status was associated with longer overall survival (OS), P=0.04. There were no other significant associations. An almost universal overexpression of angiogenesis markers in the samples analyzed supports the evaluation of angiogenesis inhibition as a potential target for therapy. High levels of NRP-1 and HER-2 in SCCHN samples appear to be associated with decreased survival and earlier progression of disease, respectively, in SCCHN patients and may represent targets for therapy.