The inhibition of thermolysin by an optically active silicon-containing amino acid, 3-trimethylsilylalanine (TMS-Ala), and its derivatives was examined by considering the similarity of structure between TMS-Ala and leucine. Although free L- and D-TMS-Ala did not show the inhibition, several derivatives of L-TMS-Ala, especially Z-L-TMS-Ala and L-Leu-(L-TMS-Ala), exhibited a higher inhibitory activity toward thermolysin than did Z-L-Leu and L-Leu-L-Leu respectively. Effects of TMS-Ala on the activity of its derivatives and the mode of interaction between the derivatives of TMS-Ala and thermolysin are also discussed.