A double-blind, randomized, crossover study was conducted to compare the efficacy and safety of high-dose dexamethasone and high-dose metoclopramide in the treatment of chemotherapy-induced nausea and vomiting. All entered patients had no prior chemotherapy and all received inpatient emetogenic chemotherapy mainly without cisplatin. Of the 40 evaluable patients, 23 (58%) had no vomiting with dexamethasone compared with only 11 (28%) receiving metoclopramide (P less than 0.025). Dexamethasone was found to have less adverse effect than metoclopramide on patient's appetite and activity (P less than 0.025 and P less than 0.01, respectively). Twenty-one patients (53%) developed mild to severe somnolence with metoclopramide compared to only seven (18%) who experienced this adverse effect with dexamethasone (P less than 0.01). Six patients (15%) developed extrapyramidal manifestations with metoclopramide, but none with dexamethasone. Furthermore, during dexamethasone therapy, patients developed less diaphoresis, insomnia, headache and dizziness. Upon questioning patients about their preference to future use of the antiemetic drug therapy, 28 patients (70%) preferred dexamethasone, two (5%) preferred metoclopramide and 10 (25%) found no difference. We conclude that high-dose dexamethasone has a greater antiemetic activity and is more safe than high-dose metoclopramide in patients receiving emetogenic chemotherapy mainly without cisplatin.