The in vitro metabolism of N,N-dialkylamides by phenobarbital-induced rat liver microsomes yields an N-alkylamide and the corresponding aldehyde. Although, N-hydroxymethyl-N-alkylamide intermediates can be detected from N-methyl-N-alkylamides, no N-hydroxyalkyl-N-alkylamide intermediates are detected from the N,N-dialkylamide substrates. Vmax values were independent of amide structure, whereas Vmax/Km values were dependent on the lipophilicity of the N,N-dialkylbenazamide studied. These results suggest that diffusion of substrate into the membrane-bound enzyme active site limits the rate of microsomal oxidation of the amides. Metabolism of N-alkyl-N-methylamides reveals identical values of Vmax for demethylation and dealkylation. Values of Vmax/Km for demethylation depend upon the lipophilicity of the N-alkyl group, whereas Vmax/Km values for dealkylation appear to be dependent upon the steric bulk of the alkyl group, particularly around the alpha-carbon. Moreover, Vmax/Km values for demethylation are larger than for dealkylation, implying the reactions are under kinetic control. Comparison of the kinetic data with theoretical AM1 semi-empirical molecular orbital calculations suggests a mechanism involving formation of a carbon-centred radical. Use of an N-cyclopropylmethylbenzamide substrate to trap such a radical failed, presumably because oxygen rebound is faster than radical rearrangement. An N-cyclopropylamide substrate did not undergo metabolism of the cyclopropyl ring, consistent with carbon-centred radical, but not nitrogen radical cation, formation.