Fifteen patients with osteogenic sarcoma receiving high-dose methotrexate chemotherapy were studied in a randomized, double-blind, placebo-controlled trial of oral and smoked delta-9-tetrahydrocannabinol (THC) as an antiemetic. Each patient served as his or her own control. Fourteen of 15 patients had a reduction in nausea and vomiting on THC as compared to placebo. Delta-9-tetrahydrocannabinol was significantly more effective than placebo in reducing the number of vomiting and retching episodes, degree of nausea, duration of nausea, and volume of emesis (P less than 0.001). There was a 72% incidence of nausea and vomiting on placebo. When plasma THC concentrations measured less than 5.0 ng/mL, 5.0 to 10.0 ng/mL, and greater than 10.0 ng/mL, the incidences of nausea and vomiting were 44%, 21%, and 6%, respectively. Delta-9-tetrahydrocannabinol appears to have significant antiemetic properties when compared with placebo in patients receiving high-dose methotrexate.