The effects of ethyl alcohol on the interaction of gliclazide and other sulfonylureas with bovine serum albumin (BSA) were studied by use of an equilibrium dialysis technique. The strongest inhibition of gliclazide-binding with BSA was induced at the drug level which corresponded to the effective dose in the presence of ethyl alcohol (1 mg/ml), resulting in a 2.5-fold higher level of free gliclazide than that of the control. The ratio (Df/Dt) of free gliclazide concentration to total gliclazide concentration in the medium was constant (about 30%) at concentrations of ethyl alcohol over 0.5 mg/ml. The ratio of Df/Dt of tolubutamide, glyclazide, acetohexamide and glycopyramide with BSA was raised (+Δ2.1-19.8%) in each case, whereas that of chlorpropamide or tolazamide was lowered (-Δ2.9-6.2%) by the addition of ethyl alcohol. The addition of ethyl alcohol to the medium reduced the gliclazide-binding ability in the primary binding site on the BSA molecule and reduced the association constant to 2.5×103 M<-1> (56.8%) from 4.4×103M-1 of the control. In conclusion, it is suggested that one of the reasons for the enhancing effect of ethyl alcohol on the hypoglycemic action of sulfonylurea is the inhibition of binding of the drug with blood protein.