Objectives/Hypothesis: MK-2206 is an orally active, allosteric inhibitor of AKT, a component of the phosphatidylinositol-3 kinase (PI3K) pathway. The PI3K-AKT pathway is a downstream signaling pathway that has recently been found to play an important role in head and neck squamous cell carcinoma (HNSCC). The objective of this study is to examine the role AKT inhibition may play in treatment of HNSCC. Study Design: In vivo and in vitro study. Methods: Cell migration after 24-hour treatment with subtherapeutic doses of MK-2206 was assessed using an enzyme-linked immunosorbent assay in four HNSCC cell lines: CAL27, FaDu, SCC-1, and SCC-5. In vitro effect of MK-2206 on cell migration was assessed by making linear scratches in culture plates after cell lines were grown to confluency. Images were taken at 8, 16, and 24 hours. In vivo analysis was performed on nude mice with human SCC1-orthotopic tongue tumors. After tumors were allowed to grow for 7 days, mice were treated with oral dosing of 120 mg/kg of MK-2206 every other day for 2 weeks. Tumor size was assessed after each treatment using a pair of digital calipers. At the end of the treatment period, mice were sacrificed and cervical lymph nodes were assessed for metastasis using fluorescent imaging of tumor cell markers. Results: Subtherapeutic doses of MK-2206 were sufficient to significantly reduce cell migration in FaDu, SCC-1, and SCC-5 cell lines (P <.001) but not in Cal27 (P =.09). In vitro scratch test results in SCC-1 cells yielded significant reduction in cell movement at 8, 16, and 14 hours (P <.001). In vivo orthotopic model yielded significant reduction in primary tumor size (P =.04) and reduction in positive cervical lymph nodes (P =.01) between treatment and control mice. In addition we found 100% survival of MK-2206 treated mice after 2 weeks of treatment compared with 70% survival in our control group (P =.03). Conclusions: Treatment with MK-2206 is sufficient to inhibit HNSCC chemotaxis and migration in vitro. In an orthotopic model, treatment with MK-2206 reduces primary tumor size and cervical metastasis while improving survival. MK-2206 currently is being used in phase II clinical trials for combination treatment of metastatic solid tumors and may be useful for treating HNSCC as well. Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.