Head and neck squamous cell carcinoma (HNSCC) is a common type of cancer. Better understanding of molecular aberrations associated with HNSCC might identify new diagnostic and therapeutic strategies for this disease. In this study, we found ubiquitin-specific protease 4 (USP4) was significantly upregulated in HNSCC. USP4 negatively regulates RIP1-mediated NF-kappaB activation and promotes TNF-alpha-induced apoptosis in FaDu cells. USP4 directly interacts with receptor-interacting protein 1 (RIP1) and deubiquitinates K63-linked ubiquitination from RIP1. Therefore, our results indicate that USP4 has tumor suppressor roles in HNSCC and suggest USP4 as a potential therapeutic target for HNSCC.