BACKGROUND: Two-phase partitioning bioreactors (TPPBs) employ an immiscible phase to partition toxic substrates/products to/away from cells to reduce cytotoxicity and improve bioprocess performance. Initially, immiscible organic solvents were used as the sequestering phase, and their selection included consideration of solutesolvent affinity, which can be predicted through first principles consideration of solute activity and phase equilibrium thermodynamics. Polymers can replace organic solvents in such systems, however, their selection has largely been via heuristic means, and a more fundamental approach is necessary for future success in rational polymer identification. RESULTS: Material properties (polymer crystallinity, solubility parameter, and glass transition temperature Tg) were examined across several polymers and polyaromatic hydrocarbons as target solutes. All were shown to influence solutepolymer affinity. CONCLUSION: This first attempt at identifying physical/chemical properties that affect solutepolymer partitioning has been able to demonstrate some clear trends, and has allowed us to formulate a polymer selection guide, based on first principles, to facilitate the selection of solutepolymer pairs for solidliquid TPPB applications. Copyright (C) 2012 Society of Chemical Industry