The COSMO-RS methodology was used to perform a screening of ionic liquids as the most effective media for extraction of methylxanthines from natural sources. The computational methodology was validated based on the values of experimentally obtained extraction yields of caffeine from guarana seeds. A linear dependence between the extraction yields and computed thermodynamic activity coefficients of caffeine was found. A total of 23 cations and 38 anions commonly used in ionic liquids were used in the studies comprising a total of 874 ionic liquids. It was found that the ionic liquid based on the 1-dodecyl-3-methylimidazolium cation and tetraphenyl borate anion was responsible for the best extraction efficiency equal to 10.1 wt%, which is more than 50% higher than the best experimentally studied ionic liquid. Furthermore, the effectiveness of recyclability of methylxanthines from the aqueous solutions of ionic liquids was modeled. It was found that the partition coefficient values of caffeine are a good qualitative measure of re-extraction efficiency of the solvents. Since ionic liquids with high extraction efficiency have a strong affinity towards aqueous solutions, while those with high recyclability towards the organic phase it is indispensable to take both these steps into account when modeling the extraction process. (C) 2017 Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.