A two-centre prospective randomized open cross-over study to compare granisetron (Gra) vs ondansetron (Ond) vs tropisetron (Tro) in the prevention of high-dose cisplatin-induced nausea and vomiting was carried out. The notable characteristics of our study were: all patients were very homogeneous for tumor site (head and neck cancer), all were treated with high-dose (80 to 100 mg/sqm) cisplatin on day 1 and all were chemotherapy-naive. 141 patients for a total number of 541 chemotherapy cycles containing high-dose cisplatin were randomized to receive 24 mg of Ond intravenously (i.v.) or 3 mg of Gra i.v. or 5 mg of Tro i.v. for the control of acute nausea and emesis. In the Gra group in 138 out of 193 cycles (71.5%) the patients experienced a complete response (CR), in 34 cycles (17.6%) a major response (MR), in 9 cycles, (4.7%) a minor response (MiR) and in 12 cycles (6.2%) a failure (F). In the Ond group in 126 out of 176 cycles (71.6%) the patients experienced a CR, in 35 cycles (19.9%) an MR, in 5 cycles (2.8%) a MiR and in 10 cycles (5.7%) a F. In the Tro group in 115 out of 172 cycles (66.9%) the patients experienced a CR, in 30 cycles (17.4%) a MR, in 18 cycles (10.5%) a MiR and in 9 cycles (5.2%) a F. The major efficacy (CR + MR) was achieved in 172 out of 193 cycles (89.1%) for Gra, in 161 out of 176 cycles (91.5%) for Ond and in 145 out of 172 cycles (84.3%) for Tro. The statistical analysis could detect a significant difference as for major efficacy only between Ond and Tro (P<0.05, CI 95%: +0.4/+14%): the Ond indeed was more effective than Tro. Moreover, as far as the MiR were concerned, both Gra and Ond were more effective than Tro (P<0.05, CI95%: –11/–0.3%, –13/–2%, respectively). All other comparisons between the three antiemetics did not show significant differences. Our results, although achieved in an “open” trial, show that Gra and Ond are equally effective antiemetic agents against acute nausea and vomiting as for complete control and major efficacy. Tropisetron is equally effective as Gra and Ond as for complete control but it is slightly less effective than Ond as for major efficacy. All three antiemetics can be safely administered to patients undergoing highly emetogenic chemotherapy.Work supported by CNR, Rome, AP. ACRO, Contract No. 94.01157.PF39.