Mass drug administration has been less successful as a technique for controlling intestinal schistosomiasis (S. mansoni) than anticipated. In Uganda, the mass distribution of praziquantel has been provided to populations at risk of infection since the early 2000s, but prevalence mostly remains high. This is the case, for example, at locations in north-western and south-eastern Uganda. However, there is a remarkable exception. Among Madi fishing populations and their immediate neighbours, living close to the border with South Sudan, the rate of infection has dropped dramatically. A parasitological survey carried out at twelve fishing sites in 2013 identified only three cases of S. mansoni among 383 adults tested. This article asks: why is the prevalence of S. mansoni so low among fisherfolk in northern Uganda? Taking a biosocial approach, it suggests that the mass distribution of drugs, free of charge, has had an impact. However, the low prevalence of infection cannot be attributed to this alone. Other important factors may also have contributed to the decline in infection. These include changing fishing livelihoods, local attitudes to public health interventions, access to water and sanitation facilities, hygiene practices and the use of anti-malarial treatments. Above all, the article highlights the importance of investigating both social and biological dimensions of infection simultaneously, and of recognizing the local complexities of sustainably treating this debilitating parasitic disease.