Here, we conducted a functional RNAi screen to identify regulators of TNFα-induced NF-κB activation and cell viability, using parallel NF-κB β−lactamase reporter and cell viability assays in a HNSCC cell line which harbors expression and genomic alterations typically found in human papillomavirus–negative HNSCC. The gene discussed is TNF; the disease is head and neck squamous cell carcinoma.