Cetuximab, a monoclonal antibody to the epidermal growth factor receptor (EGFR), extends survival in combination with standard therapy in head and neck squamous cell carcinoma (HNSCC). However, as effects are modest, and patients experience side effects, a biomarker to predict resistance and personalize therapy is needed. Activation of signaling pathways downstream from receptor tyrosine kinases predicts resistance to such therapies in other cancers. The most common abnormalities downstream from EGFR in HNSCC are in the PI3K pathway, activated via loss of expression of the regulator PTEN, or via PI3K mutation. We studied whether PTEN and/or PI3K abnormalities predict resistance to cetuximab.