AbstractThermolysin catalyzed solid‐to‐solid synthesis of the model peptide Z‐L‐Phe‐L‐Leu‐NH2 is practically feasible in water and a range of organic solvents with different physicochemical properties. Excellent overall conversions were obtained in acetonitrile, ethyl acetate, n‐hexane, methanol, 2‐propanol, tert‐amyl alcohol, tetrahydrofuran, toluene and water, while no product precipitation was observed in dichloromethane resulting in a much lower yield. In precipitation driven synthesis the product accumulates both in solution and in the solid phase. It was shown that the highest overall yields (yield in the liquid plus yield in the solid) can be expected in solvents where the substrate solubilities are minimized. The best yields of solid product can be expected in solvents where both product and substrate solubilities are lowest. This was in agreement with experimental observations and should be generally valid. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 80: 509–515, 2002.