In this study we hypothesized that methylation of key genes is a molecular mechanism leading to cisplatin resistance. We decided to investigate DNA methylation as a resistance mechanism because it is reversible by available drugs. We used SCC-25 and its cisplatin-resistant counterpart, SCC-25/CP, and determined that pre-treatment with the demethylating drug decitabine enhanced the anti-proliferative and apoptotic effect of cisplatin on these cell lines. In our HNSCC mouse model, combination treatment with decitabine and cisplatin produced a more robust anti-tumor effect than either drug alone. Decitabine pre-treatment in vitro reversed cisplatin-resistance in SCC-25/CP cells, and lowered the dose of cisplatin required to produce antiproliferative or apoptotic effects. Interestingly, decitabine pretreatment also lowered the dose of cisplatin required for cisplatinsensitive SCC-25 cells. The clinical significance of our results is that decitabine could salvage patients with cisplatin-resistant tumors; moreover, allowing for reduced toxicity. Previous studies have explored the effectiveness of epigenetic therapy in rescuing cisplatin resistance in other cancers. Adding hydralazine and valproate to cisplatin therapy significantly increased progression-free survival in advanced stage cervical cancer patients. A phase I trial for patients with solid tumors showed that combination treatment of decitabine followed by carboplatin is safe. A phase II study adding valproate and hydralazine to the same schedule of chemotherapy on which patients with solid cancers were progressing showed clinical benefit in 12 of 15 patients. At the same time there have been studies adding demethylating agents to platinum-based chemotherapy with negative results. A phase II trial randomized ovarian cancer patients progressing 6–12 months after previous platinum therapy to one of two groups: one group would receive decitabine with carboplatin, and the second group would receive carboplatin alone. However the study closed after an interim BMS-907351 analysis showed that the combination group had lack of efficacy and poor treatment deliverability. Our dose scheduling of decitabine and cisplatin is based on previous work in ovarian and colon carcinoma showing that multiple doses of decitabine are required prior to cisplatin administration to maximally sensitize xenografts to cisplatin. In addition to reduced survival, head and neck cancer patients have significant function-limiting pain, which is either cancerinduced or treatment-induced. While survival and pain seem like unrelated issues, a recent randomized clinical trial shows that aggressive pain management in advanced-stage cancer patients significantly improves quality of life and increases survival. Peripheral neuropathy is a major toxic side effect of cisplatin and contributes to pain. The behavioral assay that we used on our preclinical model detects both cancer-induced pain and neuropathic pain. We showed that combination therapy of decitabine and cisplatin resulted in significantly reduced mechanical pain. While nociception in our preclinical model was likely cancer-induced, decitabine treatment potentially reduces the required cisplatin dose, thus minimizing peripheral neuropathy.