This article presents a detailed study of the role of solid state surface chemistry on the high shear granulation performance of organic pharmaceutical solids. The sole effect of powder surface chemistry on granulation performance was investigated by coagglomerating untreated and silanized D-mannitol powder from a narrow sieve fraction in a high shear process. The wetting performance by polyvinylpyrrolidone (PVP) binder solutions was quantified using experimentally determined thermodynamic spreading coefficients, calculated from surface energy heterogeneity distributions obtained via inverse gas chromatography (IGC) measurements. Increases in binder wettability of the formulations correlated with increases in both granule size and compressive elastic moduli, which are attributed to an increase in interparticle contacts. In conclusion, starting materials surface chemistry plays a crucial role in final granule properties, even in highly agitated processes such as high shear granulation. The comprehensive characterization of powder surface properties is necessary to facilitate the manufacture of granules with controllable critical attributes.