Annual school-based mass drug administration with praziquantel has been widely implemented to control schistosomiasis, but other treatment strategies could have a different impact. The aim of this study was to investigate the impact of six different treatment strategies on Schistosoma mansoni infection in a cluster-randomized controlled trial in schoolchildren, in a high transmission area of the Mwanza Region, Tanzania. A total of 150 villages were randomized into six arms with 25 villages in each arm. In each village, approximately 100 schoolchildren aged 9-12 years were randomly selected each year and investigated for S. mansoni prevalence and intensity based on three consecutive stool samples using the duplicate Kato-Katz technique. Four years of community-wide treatment (CWT) was the most intensive treatment strategy, whereas 2 years of school-based treatment (SBT) combined with 2 years without treatment (holiday) was the least intensive treatment. The remaining strategies constituted different combinations of CWT, SBT, and holiday years. Baseline results on S. mansoni infection were obtained from 14,620 schoolchildren from 148 villages, and mean prevalence and mean intensity among infected were 48.6-60.6% and 130.5-229.8 eggs per gram, respectively. Over the years, mean prevalence and mean intensities declined in all arms, but when comparing year 5 mean prevalence and mean intensity, there were no statistically significant differences between treatment arms. Thus, measured in a random selection of schoolchildren aged 9-12 years, four times CWT was not superior to four times SBT, while 2 years of treatment holiday combined with 2 years of SBT had the same impact as 4 years of SBT.