OBJECTIVE: As a protective response, during starvation organisms withdraw energy from growth and reproduction to focus on cellular maintenance. Cancer cells cannot undergo this differential response which has been theorized as an adjunct to improve both the effect of chemotherapy treatment and reduce treatment side effects. We sought to investigate the feasibility and effect of short-term fasting in patients receiving chemotherapy for gynecologic malignancy. METHODS: A randomized control trial was conducted of women with gynecologic malignancies receiving at least 6 planned chemotherapy cycles. Fasting patients maintaining a water-only fast for 24 h before and 24 h following each chemotherapy cycle were compared to nonfasting patients. Treatment related side effects and quality of life (QOL) was assessed using NCCN-FACT FOSI-18 questionnaire. RESULTS: Analysis included data from 120 cycles of chemotherapy. The majority of patients had stage 3 and 4 malignancy requiring multi-agent chemotherapy. Eleven patients had ovarian, 8 had uterine, and 1 had cervical cancer. Ninety percent received taxane and platinum-based doublet therapy. Weight loss and unanticipated hospitalizations were similar between treatment groups. Fewer dose reductions or delays were seen in the fasting group. There was no significant difference in mean QOL scores, but fasting group QOL scores improved over the course of treatment to a level that reached the minimal clinically important difference. CONCLUSION: A 48-h fast is well tolerated without increasing weight loss, hospital admissions, or chemotherapy dose reduction/delays. Fasting resulted in fewer treatment modifications and improved quality of life scores over the course of treatment.