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<p>Abstract</p> <p>Background</p> <p>Schistosomiasis and soil-transmitted helminthiasis (STH) are among the neglected tropical diseases in Africa. A national control program for these diseases was initiated in Uganda during March 2003. Annual treatment with praziquantel and albendazole was given to schoolchildren in endemic areas and to adults in selected communities where local prevalence of <it>Schistosoma mansoni </it>in schoolchildren was high.</p> <p>Methods</p> <p>The impact of the treatment program was monitored through cohorts of schoolchildren and adults. Their infection status with <it>S. mansoni </it>and STH was determined by parasitological examinations at baseline and at annual follow-ups. The prevalence and intensity of <it>S. mansoni </it>and STH before and after treatment were analyzed.</p> <p>Results</p> <p>Two rounds of treatment significantly reduced the prevalence of <it>S. mansoni </it>infection in schoolchildren across three regions in the country from 33.4–49.3% to 9.7–29.6%, and intensity of infection from 105.7–386.8 eggs per gram of faeces (epg) to 11.6–84.1 epg. The prevalence of hookworm infection was reduced from 41.2–57.9% to 5.5–16.1%, and intensity of infection from 186.9–416.8 epg to 3.7–36.9 epg. The proportion of children with heavy <it>S. mansoni </it>infection was significantly reduced from 15% (95% CI 13.4–16.8%) to 2.3% (95% CI 1.6–3.0%). In adults, significant reduction in the prevalence and intensity of <it>S. mansoni </it>and hookworm infections was also observed. More importantly, the prevalence and intensity of both <it>S. mansoni </it>and hookworm infections in the cohorts of newly-recruited 6-year-olds who had never previously received treatment decreased significantly over 2 years: 34.9% (95% CI 31.9–37.8%) to 22.6% (95% CI 19.9–25.2%) and 171.1 epg (95% CI 141.5–200.7) to 72.0 epg (95% CI 50.9–93.1) for <it>S. mansoni</it>; and 48.4% (95% CI 45.4–51.5) to 15.9% (95% CI 13.6–18.2) and 232.7 epg (95% CI 188.4–276.9) to 51.4 epg (95% CI 33.4–69.5) for hookworms, suggesting a general decline in environmental transmission levels.</p> <p>Conclusion</p> <p>Annual anthelminthic treatment delivered to schoolchildren and to adults at high risk in Uganda can significantly reduce the prevalence and intensity of infection for schistosomiasis and STH, and potentially also significantly reduce levels of environmental transmission of infection.</p>