In this study, the origins of granule content non-uniformity in the high-shear wet granulation of a model two-component pharmaceutical blend were investigated. Using acetaminophen as the active pharmaceutical ingredient (API) and microcrystalline cellulose as the excipient, the distribution of the API across the granule size classes was measured for a range of conditions that differed in the duration of the initial dry mixing stage, the overall composition of the blend and the wet massing time. The coarse granule fractions were found to be systematically sub-potent, while the fines were enriched in the API. The extent of content non-uniformity was found to be dependent on two factors – powder segregation during dry mixing and redistribution of the API between the granule size fractions during the wet massing phase. The latter was demonstrated in an experiment where the excipient was pre-granulated, the API was added later and wet massed. The content non-uniformity in this case was comparable to that obtained when both components were present in the granulator from the beginning. With increasing wet massing time, the extent of content non-uniformity decreased, indicating that longer wet massing times might be a solution for systems with a natural tendency for component segregation.