Schistosomiasis japonica remains a significant public-health problem in China. This study evaluated cost-effectiveness of a comprehensive schistosomiasis control program (2003-2006). The comprehensive control program was implemented in Zhangjia and Jianwu (cases); while standard interventions continued in Koutou and Xiajia (controls). Incurred costs were documented and the schistosomiasis comprehensive impact index (SCI) and cost-effectiveness ratio (Comprehensive Control Program Cost/SCI) were applied. In 2003, prevalence of Schistosoma japonicum infection was 11.3% (Zhangjia), 6.7% (Jianwu), 6.5% (Koutou), and 8.0% (Xiajia). In 2006, the comprehensive control program in Zhangjia and Jianwu reduced infection to 1.6% and 0.6%, respectively; while Koutou and Xiajia had a schistosomiasis prevalence of 3.2% and 13.0%, respectively. The year-by-year SCIs in Zhangjia were 0.28, 105.25, and 47.58, with an overall increase in cost-effectiveness ratio of 374.9%-544.8%. The SCIs in Jianwu were 16.21, 52.95, and 149.58, with increase in cost-effectiveness of 226.7%-1,149.4%. Investment in Koutou and Xiajia remained static (US$10,000 unit cost). The comprehensive control program implemented in the two case villages reduced median prevalence of schistosomiasis 8.5-fold. Further, the cost effectiveness ratio demonstrated that the comprehensive control program was 170% (Zhangjia) and 922.7% (Jianwu) more cost-effective. This work clearly shows the improvements in both cost and disease prevention effectiveness that a comprehensive control program-approach has on schistosomiasis infection prevalence.