The influence of the solvent on the molecular recognition capability of molecularly imprinted polymers (MIPs) was studied. The energy difference (Delta E) of a molecule in vacuum and in a given solvent was calculated using density functional theory (DFF) at B3LYP/6-31+G** level, and used as a measure of the affinity of the solvent to the molecule. The AE of the template molecule, theophylline (THO), in three of the most extensively used solvents, chloroform, tetrahydrofuran (THF) and dimethyl sulfoxide (DMSO), was calculated, in which chloroform gave the smallest AE and DMSO gave the largest. The same order for AE was obtained for the monomer, methacrylic acid (MAA), in the three solvents. The calculated results indicate that chloroform is the most suitable solvent for the preparation of MIP for THO. DMSO, however, is not since it has high affinities to THO and MAA, and these inhibit the interaction between the THO and MAA. To examine the validity of the simulated results, MIPs for THO were synthesized in the three solvents and used for the adsorption of THO, respectively. The MIP synthesized in chloroform showed the maximum selectivity while that synthesized in DMSO showed the worst, in agreement with the above molecular simulation. H NMR spectroscopy showed that the H-bond between THO and MAA is the major force in molecular recognition, and this can be much affected by the solvent. The results above are of fundamental importance for the development of MIPs. (c) 2007 Elsevier B.V. All rights reserved.