We conducted a prospective cohort study in Leyte, the Philippines, among 611 Schistosoma japonicum-infected participants 7–30 years old, all of whom were treated with praziquantel at baseline. To detect hepatic fibrosis, abdominal ultrasound was performed at baseline and 12 months after treatment. Stool for assessment of S. japonicum infection was collected at baseline and at 3, 6, 9, and 12 months after treatment. Cytokines (interleukin [IL]-4, IL‐5, IL‐10, IL‐13, tumor necrosis factor-α, and interferon‐γ) produced by peripheral‐blood mononuclear cells in response to soluble worm antigen preparation (SWAP), soluble egg antigen (SEA), and control medium were measured once 4 weeks after treatment. IL‐4 to SWAP and IL‐10 to both SWAP and SEA were associated with the presence of baseline fibrosis after adjustment for potential confounding variables (, for all). In participants with fibrosis at baseline, IL‐4 to SWAP and IL‐5 and IL‐13 to both SWAP and SEA were associated with persistent fibrosis at 12 months after treatment (, for all). Males showed consistently stronger T helper 2 (Th2) cytokine responses to both SWAP and SEA than did females (, for all). These results suggest an independent role for Th2‐biased cytokine responses to S. japonicum antigens in persistent hepatic fibrosis and indicate that Th2 cytokines may contribute to the male‐biased prevalence of fibrosis.