This phase II trial assessed the cardiovascular safety and tolerability of high-dose granisetron for the treatment of nausea and vomiting in cancer patients undergoing emetogenic chemotherapy. Forty-one patients were given 30-min infusions of granisetron, 40 or 120 μg/kg i.v., as either a single dose or as split doses, at 6-h intervals. Subsequently, patients had the option of the alternative dosing regimen or to return to conventional antiemetic therapy. Patients were monitored for 24 h following the first granisetron infusion. Electrocardiogram (ECG; lead II and Holter monitoring) measurements were made during the study and blood samples for pharmacokinetic analysis were taken at regular intervals for 48 h after the start of the first granisetron infusion. During the first chemotherapy session, granisetron was administered as: (i) bolus doses of 80 μg/kg (n=3) and 120 μg/kg (n=19) or (ii) split doses of 2×40 μg/kg (n=1) and 3×40 μg/kg (n=18). Crossover therapy was administered to 22 patients, with granisetron doses of 120 μg/kg (n=12), 2×40 μg/kg (n=1) and 3×40 μg/kg (n=9). We conclude that supra-therapeutic doses up to 120 μg/kg granisetron had no clinically significant effect on ECG, pulse rate or blood pressure. The treatment was well tolerated with no significant changes in biochemistry or hematological parameters.