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Objective: To evaluate the effect of a comprehensive schistosomiasis control strategy based on buffalo removal in a lake and marshland region., Methods: A community intervention trial was carried out in seven pilot villages and seven control villages along Dongting Lake in Anxiang County, Hunan Province. Besides annual routine control measures such as synchronous chemotherapy, molluscicidal spray and health education, all buffaloes and sheep were killed or removed from the pilot areas in 2005, of which the effect was strengthened by other supporting measures such as replacing bovines by agricultural machines, isolating meadows and prohibiting pastures, supplying safe water, and building sanitary lavatories or methane pits. Schistosoma japonicum infection in humans or Oncomelania snails was observed and followed up to the spring of 2011., Results: Three years after the intervention, the infection rates in humans decreased to below 1% with no infected snails found outside the embankment in the pilot villages, but the infection rates still ranged between 2% and 3% in the control villages 4 years after the intervention. The comprehensive measures centered on buffalo removal exempted about 50% of the population from the infection in pilot villages., Conclusion: Buffalo removal is the key element of comprehensive control strategy which could accelerate the control process and promote the elimination of schistosomiasis in lake and marshland regions along the Yangtze River.