Background: Chemotherapy-induced nausea and vomiting (CINV) remains a clinical management problem after treatment with highly emetogenic chemotherapy (HEC). We therefore designed and carried out a multicentre, randomised, double-blind, placebo-controlled trial to assess whether a three-drug antiemetic regimen of ondansetron, dexamethasone, and the neurokinin-1-receptor antagonist casopitant mesylate was able to prevent acute and delayed CINV events in patients naive to chemotherapy with a malignant solid tumour who were scheduled to receive cisplatin-based HEC regimens. Methods: The study was done between Nov 6, 2006, and Oct 9, 2007, in 77 participating centres in 22 countries. All 810 patients enrolled in the trial received dexamethasone and ondansetron. Patients were randomly assigned to also receive placebo (n=269), single oral dose of casopitant mesylate (150 mg oral, n=271), or 3-day intravenous plus oral casopitant mesylate (90 mg intravenous on day 1 plus 50 mg oral on days 2 and 3, n=270). Randomisation was done using a central telephone system at the study level, because some centres were expected to recruit only a few patients during the study period. The primary endpoint was the proportion of patients achieving complete response (no vomiting, retching, or use of rescue medications) in the first 120 h after receiving HEC. Efficacy analysis was done on the modified intention-to-treat population (n=800), which included all patients who received placebo or study drug and HEC (n=265 control, n=266 single-dose oral casopitant mesylate, n=269 3-day intravenous and oral casopitant mesylate). Safety was reported in 802 patients who received either placebo or study medication. This study is registered with ClinicalTrials.gov, NCT00431236. Findings: Significantly more patients in each casopitant group achieved complete response in cycle 1 of HEC treatment than did those in the control group (175 [66%] patients in the control group, 228 [86%] in the single-dose oral casopitant mesylate group [p<0·0001 vs control], and 214 [80%] in the 3-day intravenous plus oral casopitant mesylate group (p=0·0004 vs control]). This improvement was sustained over multiple cycles of HEC. Adverse events occurred in 205 (77%) patients in the single-dose oral casopitant mesylate group and 203 (75%) patients in the 3-day intravenous and oral casopitant mesylate group compared with 194 (73%) of patients in the control group. The most common serious adverse events were neutropenia (n=5 [3%] in the control group, n=3 [1%] in the single-dose oral casopitant mesylate group, and n=11 [4%] in the 3-day intravenous plus oral casopitant mesylate group), febrile neutropenia (n=1 [<1%] in the control group, n=4 [1%] in the single-dose oral casopitant mesylate group, and n=6 [2%] in the 3-day intravenous plus oral casopitant mesylate group), and dehydration (n=4 [2%] in the control group, n=2 [<1%] in the single-dose oral casopitant mesylate group, and n=1 [<1%] in the 3-day intravenous plus oral casopitant mesylate group). Interpretation: A three-drug regimen including a single oral dose or 3-day intravenous plus oral regimen of casopitant mesylate plus dexamethasone and ondansetron significantly reduced CINV events in patients receiving HEC compared with a two-drug regimen of dexamethasone and ondansetron. Funding: GlaxoSmithKline.