The microsomal epoxide hydrolase (mEH)-catalyzed hydrolysis of cis-4,4'-dimethylstilbene oxide (1a), cis-4,4'-diethylstilbene oxide (1b), cis-4,4'-diisopropylstilbene oxide (1c), and cis-4,4'-dichlorostilbene oxide (1d) have been investigated using rabbit liver microsomal preparations. The kinetic parameters, Km and Vmax, and the absolute stereochemistry of the reactions have been determined and compared with those of cis-stilbene oxide (1e). All epoxides 1a-d are hydrolyzed by mEH with high product enantioselectivity to give (R,R)-(+)-diols with ee > or = 90%. The presence of the substituents on the phenyl rings markedly reduces the rates of mEH catalyzed hydrolysis with respect to cis-stilbene oxide, by increasing Km and reducing Vmax in the cases of 1a, 1b, and 1d, or reducing only the Vmax in the case of 1c. The very low Vmax, together with a persistent ability to fit into the mEH active site, make all these epoxides, and particularly 1c, inhibitors of cis-stilbene oxide hydrolysis. The kinetic and stereochemical results are interpreted on the basis of the proposed topology of the mEH active site.