AbstractPrevious work reported that commercial dental composite resins containing a urethane‐modified bisGMA (bisphenylglycidyl dimethacrylate)/TEGDMA (triethylene glycol dimethacrylate) (ubis) based monomer system showed a 10‐fold reduction in the release of a bisGMA‐derived product, bishydroxypropoxyphenyl propane (bisHPPP), as compared with that found for bisGMA/TEGDMA (bis) based composites after incubation with cholesterol esterase (CE). Unfortunately, these materials also differed substantially in filler type and content, making it impossible to directly relate any specific parameter to the differences in biodegradation levels. By controlling for filler content and type, the current study will seek to probe the biomolecular interactions between composite resin chemistry and esterase activity in order to help explain the observed differences in biodegradation levels between the ubis and bis resin systems. After 32 days of incubation, buffer and CE solutions were analyzed for degradation products using high‐performance liquid chromatography, UV spectroscopy, and mass spectrometry. Both materials were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, and X‐ray photoelectron spectroscopy. In the CE groups, the ubis system showed a 2.6‐ to 86‐fold reduction (dependent on the product) in the amount of isolated products relative to the bis system (p < 0.01). Scanning electron microscopy data also demonstrated the relative stability of the ubis system and X‐ray photoelectron spectroscopy analysis showed a higher content of the ester bond at the surface of the bis samples. Fourier transform infrared data showed that both resins had similar conversions. Because both systems were identical except for their monomer systems, it was concluded that changes in biostability were associated with chemistry. Crosslinking, hydrophobicity, and solubility all relate to ubis's pro‐stability. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 69A: 233–246, 2004