The diffusion of deuterated hexane in conformational isomers of a heterogeneous polymer, H12MDI (4,4'-dicyclohexylmethane diisocyanate)BD (1,4-butanediol)/PTMO (poly(tetramethylene oxide)), was investigated at a fixed hard segment content of 30 wt % and compared to the diffusion of acetonitrile. The effective diffusion coefficient of acetonitrile decreases with increasing trans-trans isomer content while that for deuterated hexane remains constant. These results suggest that the trend observed from acetonitrile diffusion is a function of penetrant-polymer interactions and not tortuosity effects. A model with penetrant-polymer binding to the surface of the dispersed hard segment domains of the heterogeneous polymer was developed to elucidate the main factors contributing to the interaction or hindrance effect, which were determined to be the "available" surface binding sites and the surface-to-volume ratio of the hard segment domains. FTIR-ATR spectroscopy was used to quantify this interaction effect, and SAXS was used to confirm the findings.