SummaryThis study evaluated potential changes in antischistosome immune responses in children from schools that received 4 rounds of annual mass drug administration (MDA) of praziquantel (PZQ). In a repeated cross‐sectional study design, 210 schistosome egg‐positive children were recruited at baseline from schools in western Kenya (baseline group). Another 251 children of the same age range were recruited from the same schools and diagnosed with schistosome infection by microscopy (post‐MDA group). In‐vitro schistosome‐specific cytokines and plasma antibody levels were measured by ELISA and compared between the 2 groups of children. Schistosome soluble egg antigen (SEA) and soluble worm antigen preparation (SWAP) stimulated higher IL‐5 production by egg‐negative children in the post‐MDA group compared to the baseline group. Similarly, anti‐SEA IgE levels were higher in egg‐negative children in the post‐MDA group compared to the baseline group. Anti‐SEA and anti‐SWAP IgG4 levels were lower in egg‐negative children in the post‐MDA group compared to baseline. This resulted in higher anti‐SEA IgE/IgG4 ratios for children in the post‐MDA group compared to baseline. These post‐MDA immunological changes are compatible with the current paradigm that treatment shifts immune responses to higher antischistosome IgE:IgG4 ratios in parallel with a potential increase in resistance to reinfection.