Protein Kinase B (Akt) is involved in many different intracellular functions including, cell cycle progression, cell survival, and glucose metabolism. Akt is also found to be upregulated in numerous cancer types, more especially in Head and Neck Cancers (HNSCC). Perifosine is an oral chemotherapeutic drug that affects tumor proliferation and viability by inhibiting the Akt pathway. However, Perifosine’s use within the clinics has been limited due to the development of tumor resistance. Because the Akt pathway is critical for glucose metabolism, the purpose of this study is to investigate the role of glucose metabolism in Perifosine resistance in HNSCC cells. During the experiment we found that Perifosine resistant CAL-27 (PRC) cells had an increased proliferation rate and glucose consumption rate when compared to the Perifosine sensitive (PSC) cell line. We also found that activated Akt (pAkt) expression was not inhibited in the PRC’s when treated with 5 μM Perifosine when compared to the PSC’s. In addition, pAkt expression was increased in PRC’s vs. PSC’s at baseline levels. Furthermore, the glucose inhibitor Phloretin (20 and 2 μM for 48 hours) was able to sensitize the PRC’s to 5 μM Perifosine treatment. In conclusion, increased glucose metabolism could be correlated to Perifosine resistance in HNSCC. These results suggest that a glucose inhibitor such as Perifosine could be used in combination with Akt inhibitors as novel chemotherapeutic regimen in HNSCC treatment. "