The effect of sulfisoxazole on the propofol response has been investigated in an animal model. Doses of propofol (0, 50, 75 and 100 mg/Kg intraperitoneal route) were administered to control (n = 36) and sulfisoxazole pretreated mice (n = 36). The impairment of righting reflex and struggle response were evaluated before and 5, 10, 15, 20, 30, 40, 50 and 60 minutes after propofol administration. Ten minutes after administration of the different doses of propofol, total plasma concentration was measured in both groups by high performance liquid chromatography Protein binding displacement was evaluated in vitro by the ultrafiltration technique. Pretreatment with sulfisoxazole produced an important enhancement in the effect of propofol in both tests. This change was reflected in a significant increase in the area under the time-effect curve (p < 0.001) and in a shift of the log dose-effect relationship to the left. Sulfisoxazole itself did not produce any effect on either test. ED50 for the righting reflex was significantly reduced from 114 mg/kg to 64 mg/kg in sulfisoxazole pretreated groups and it fell from 87 mg/kg to 43 mg/kg for the struggle response test. No changes in the total plasma concentration and protein binding were observed. On the basis of these results, it was concluded that a clinical interaction could be expected but this cannot be explained by an alteration in the protein binding.