The objective of the present study was to determine whether ondansetron, a specific serotonin type 3 receptor antagonist (5-HT3), relieves cholestatic pruritus in patients resistant to conventional antipruritic therapy (antihistamines and cholestyramine). In a placebo-controlled study the acute effect of an intravenous injection of ondansetron (4 mg, 8 mg) or placebo (NaCl solution) was tested in 10 patients (41-66 years of age; 4 men, 6 women) with cholestatic itch. A successful treatment was assessed when the intensity of itch was reduced by 50% or more within 2 h after injection of ondansetron. Intensity of itch was determined by the patients on a visual rating scale from 0 to 10. Ondansetron reduced or abolished pruritus within 30-60 min after injection. A 50% reduction of the intensity of itch was observed up to 6 h after injection of 8 mg. The effect was reproducible in the same patient. In conclusion ondansetron is effective in the treatment of cholestatic itch. Serotonin may participate in the generation and/or sensation of cholestatic pruritus.