Despite attempts to control intestinal schistosomiasis through school-based mass drug administration (MDA) with praziquantel using school teachers in Uganda, less than 30% of the school children take the treatment in some areas. The aim of the study was to understand why the uptake of praziquantel among school children is low and to suggest strategies for improved uptake. This was a cross-sectional qualitative study in which 24 focus group discussions and 15 key informant interviews were conducted 2 months after MDA. The focus group discussions were held with school children in twelve primary schools and the key informant interviews were held with school teachers, sub-county health assistants and the District Vector Control Officer. The study shows that the low uptake of praziquantel among school children is a result of a complex interplay between individual, interpersonal, institutional, community and public policy factors. The individual and interpersonal factors underpinning the low uptake include inadequate information about schistosomiasis prevention, beliefs and attitudes in the community about treatment of schistosomiasis and shared concerns among children and teachers about the side-effects of praziquantel, especially when the drug is taken on an empty stomach. The institutional, policy and community factors include inadequate preparation and facilitation of teachers and the school feeding policy, which requires parents to take responsibility for providing their children with food while at school, yet many parents cannot meet the cost of a daily meal due to the prevailing poverty in the area. It is concluded that strategies to improve uptake of praziquantel among school children need to be multi-pronged addressing not only the preparation and motivation of teachers and health education for children, but also the economic and political aspects of drug distribution, including the school feeding policy.