We describe the design and report baseline results of a cluster-randomized intervention to determine the importance of bovines for Schistosoma japonicum transmission in southern China. The study involves four matched village pairs in Hunan and Jiangxi Provinces, with a village within each pair randomly selected as intervention (human and bovine praziquantel treatment) or control (human praziquantel treatment only). Total study population prevalences at baseline were 12.4% (n = 5,390) and 15.2% (n = 1,573) for humans and bovines, respectively; village prevalences were similar within pairs. Bovine contamination index calculations showed that bovines less than 24 months of age were responsible for 74% of daily bovine environmental contamination with S. japonicum eggs. The village characteristics and baseline results underpin a rigorous study, which has major implications for deployment of a transmission-blocking bovine vaccine against S. japonicum. The combination of such a vaccine with other control strategies could potentially eliminate S. japonicum from southern China.