Background: Standard antiemetic therapy for chemotherapy-induced nausea and vomiting in high emetogenic chemotherapy (HEC) is a combination of NK₁ receptor antagonist, 5-HT₃ receptor antagonist and dexamethasone (DEX) on day 1-3. This study compared the efficacy of DEX on day 1 to on day 1-3 due to reduce side effects of DEX. Methods: Patients with a malignant solid tumor to receive HEC (containing > 50 mg/m² of cisplatin or anthracycline+cyclophosphamide) were randomly assigned to Arm A (DEX on day 1-3) or Arm B (DEX on day 1) with NK₁ receptor antagonist and palonosetron. Primary endpoint was complete response (CR) rate defined as no emetic episodes and no rescue medications in the overall (0-120h) phase. Secondary endpoints included CR rates in the acute (0-24h) and delayed (24-120h) phases, severity of nausea, adverse events (AEs) related to DEX and chemotherapy with CTCAE ver 4.0 on day 1-5, and quality of life with EROTC QLQ-C30 on day 5. The planned sample size of 400 provided power of 80% to detect the non-inferiority of Arm B to Arm A with the non-inferiority margin of difference by 15% in CR rate (one-sided α=0.025). Results: 401pts were enrolled and 396 pts were evaluable. Baseline characteristics were well-balanced. CR rates in the overall phase were 46.9% in Arm A and 44.0% in Arm B (risk difference: -2.9%, 95%CI: -12.6%-6.8%, P=0.007 for non-inferiority). CR rates in Arm A and in Arm B were 63.3% and 64.5% (risk difference: 1.2%, 95% CI: -8.1%-10.6%, P<0.001) in the acute phase; 56.6% and 51.5% (risk difference: -5.1%, 95% CI: -14.8%-4.6%, P=0.023) in the delayed phase, respectively. The severity of nausea was not significantly different between 2 arms on each day. AEs related to DEX depends on the duration of DEX administration: hot flushes on day 4 (P=0.013) and 5 (P=0.038) and tremor on day 5 (P=0.041) were observed more frequently in Arm A, while anorexia on day 2 (P=0.039) and 3 (P=0.006), depression on day 2 (P=0.045) and fatigue on day 2 (P=0.001) and 3 (P=0.004) were more in Arm B. Other grade >3 AEs and Global health status in QOL were similar between 2 arms. Conclusions: Administration of DEX can be limited to on day 1 in anti-emetic therapy for HEC. Clinical trial information: UMIN000008867.