Hyperammonemia is a rare adverse event of 5-FU. Here, we report a case of hyperammonemia with disturbance of consciousness during 5-FU plus nedaplatin therapy for esophageal cancer and present a literature review. A 69-year-old man was diagnosed with cT2N2M0, cStage Ⅲ esophageal cancer. He was administered with DCF therapy as the first-line neoadjuvant chemotherapy. After the first course, he showed renal dysfunction. Therefore, as the second-line neoadjuvant chemotherapy, he was administered with 5-FU plus nedaplatin. He vomited on treatment day 5 and suddenly presented with disturbance of consciousness on treatment day 6. Blood tests showed hyperammonemia(114 μg/dL). He was treated with rehydration and branched-chain amino acid solutions, resulting in a gradual improvement of symptoms. Hyperammonemia has been reported in patients with colorectal cancer but rarely in patients with esophageal cancer. A case of hyperammonemia during the 5-FU plus nedaplatin therapy has never been reported in Japan. We should be aware that 5-FU may cause hyperammonemia and resultant disturbance of consciousness during chemotherapy with 5-FU.