Background This pilot trial aimed to investigate whether modified short-term fasting (mSTF) reduces the incidence of chemotherapy-induced toxicities and whether an initial ketogenic diet (KD) as fasting supportive diet reduces the fasting-related discomfort and increases the compliance. Methods In this randomised controlled cross-over trial, gynaecologic cancer patients receiving chemotherapy with a minimum of 4 cycles were randomised to mSTF for 96 h during half of chemotherapy cycles and to consume a normocaloric diet during the other chemotherapy cycles. The caloric intake during mSTF was restricted to 25% of each patient's daily requirement. In addition, half of the patients should eat a 6-day normocaloric KD prior to each mSTF period to investigate the hunger-suppression effect of a KD. Chemotherapy-induced toxicities, fasting-related discomfort, body composition, quality of life, laboratory values, and compliance were assessed on each chemotherapy. Results Thirty patients (30-74 years) completed the study. During mSTF frequency and severity scores of stomatitis [-0.16 ± 0.06; 95% CI -0.28 - (-0.03); P = 0.013], headaches [-1.80 ± 0.55; 95% CI -2.89 – (-0.71); P = 0.002], weakness [-1.99 ± 0.87; 95% CI -3.72 – (-0.26); P = 0.024] and the score of total toxicities were significantly reduced [-10.36 ± 4.44; 95% CI -19.22 - (-1.50); P = 0.023]. Additionally, significant fewer postponements of the chemotherapy were observed post-mSTF, reflecting an improved tolerance of chemotherapy [-0.80 ± 0.37; 95% CI -1.53 – (-0.06); P = 0.034]. A significant reduction of mean body weight by -0.79 ± 1.47 kg during mSTF could not be compensated and remained until the end of study ( P <0.005). On average, Insulin [-169.4 ± 44.1; 95% CI -257.1 – (-81.8); P <0.001] and Insulin-like growth factor 1 levels [-33.3 ± 5.4; 95% CI -44.1 – (-22.5); P <0.001] significantly decreased during fasting. The KD as fasting supportive diet could neither reduce fasting-related discomfort nor increase compliance of our fasting regime. Conclusion MSTF is safe and feasible in gynaecologic cancer patients. The results indicate that mSTF during chemotherapy can reduce chemotherapy-induced toxicities and increase the tolerance of chemotherapy. Larger clinical trials are required to recommend mSTF for cancer patients.