In 2010, the Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) began the design of randomized controlled trials to compare different strategies for praziquantel mass drug administration, whether for gaining or sustaining control of schistosomiasis or for approaching local elimination of Schistosoma transmission. The goal of this operational research was to expand the evidence base for policy-making for regional and national control of schistosomiasis in sub-Saharan Africa. Over the 10-year period of its research programs, as SCORE operational research projects were implemented, their scope and scale posed important challenges in terms of research performance and the final interpretation of their results. The SCORE projects yielded valuable data on program-level effectiveness and strengths and weaknesses in performance, but in most of the trials, a greater-than-expected variation in community-level responses to assigned schedules of mass drug administration meant that identification of a dominant control strategy was not possible. This article critically reviews the impact of SCORE's cluster randomized study design on performance and interpretation of large-scale operational research such as ours.