e14632 Background: Obesity has reached epidemic proportions globally. Colon cancer is one of the leading causes of cancer related deaths in United States and obesity is associated with one-third of incidence of colon cancer. Obesity is also associated with a worse prognosis of colon cancer. However, the mechanistic details are unknown and animal models to investigate human colon cancer in the setting of obesity are lacking. Therefore, we developed a diet-induced animal model of obesity to determine whether obesity alters the efficacy of a standard colon cancer therapeutic, 5-Fluorouracil, in mice with human colon cancer xenografts. Methods: Male Rag1 mice were placed on a High Fat Western Diet (HFWD) or a Low Fat Western Diet (LFWD) for up to 12 weeks. Body weight, biochemical parameters, and glucose and insulin tolerance were measured. To determine the efficacy of 5-Fluorouracil on human colon cancer xenograft growth, Rag1 mice were fed a LFWD or HFWD for 8 weeks and then implanted with tissue-isolated HT-29 human colon cancer tumors. After 3 weeks of tumor growth, the mice were randomly assigned to a drug (5-Flurouracil 40 mg/kg) or control (normal saline) treatment group. Tumor growth was monitored for 14 days. Results: Significant differences in body weight, and glucose and insulin tolerance were observed in the four week HFWD fed mice. Obesity, glucose intolerance, and insulin resistance were more pronounced in 8 and 12 week fed HFWD mice. Estimated HT-29 human colon cancer tumor growth was significantly greater in obese HFWD fed mice compared to lean LFWD fed mice. Treatment with 5-Fluorouracil significantly reduced HT-29 human colon cancer tumor growth in lean LFWD fed mice but was without effect in obese HFWD fed mice. Conclusions: In conclusion, our findings demonstrate that diet induced obesity impairs the efficacy of 5-Fluorouracil in an obese animal model of human colon cancer. Given that obesity is growing exponentially worldwide, more studies to understand the mechanistic links between obesity and various cancers are required.