Patients undergoing chemotherapy suffer from taste disorders that affect the quality of life (QOL). In this study, a randomized, double-blind, placebo-controlled trial was conducted to explore the effectiveness of AHCC®, a standardized extract of cultured Lentinula edodes mycelia, for chemotherapy-related adverse events and taste disorders in patients with gastrointestinal cancer. Patients who received chemotherapy were randomized to receive either placebo or AHCC®. The study endpoints were the incidence of anemia and taste disorders assessed with changes in nutritional parameters. Ninety-eight patients with pancreatic ductal adenocarcinoma (PDAC) were enrolled in this study, with 55 patients randomly assigned to the AHCC® group and 43 to the placebo group. The incidence of grades 2-3 anemia in the AHCC® group who were receiving chemotherapy was not significantly different compared to that of the placebo group (Risk difference; -3.1% [95% confidence intervals (CI): -22.8% to 16.9%], p = 0.8392). In the AHCC® group, the occurrence of taste disorders during chemotherapy was significantly lower, and the nutritional parameters were significantly improved compared to those in the placebo group (Risk difference; 28.6% [95% CI: 7.5% to 47.8%], p = 0.0077). AHCC® appears to prevent taste disorders in patients with advanced PDAC who were receiving chemotherapy. AHCC® is expected to enable patients who need chemotherapy to improve nutritional status and their QOL.