Reinfection with Schistosoma mansoni following chemotherapy often results in an ameliorated granulomatous reaction and hence a mild disease. This study examined some of the immunological mechanisms that could be associated with this residual protection. BALB/c mice were infected with either a single dose (group A) of 100 S. mansoni cercariae or with 10 doses of 10 cercariae each (group B) given at 3-day intervals. The mice were treated with praziquantel 8 weeks postinfection and, 2 weeks later, together with another group of naive mice (group C), they were infected with a single dose of 100 cercariae each. All the animals were killed 8 weeks later and schistosome egg antigen (SEA)- and soluble adult worm antigen preparation (SWAP)-induced cytokine recall responses in splenocytes, as well as serum immunoglobulin levels, were quantified and hepatic granuloma sizes measured. Group A animals had higher levels of SEA-induced interferon-γ (IFN-γ) but lower levels of interleukin (IL)-5 than groups B and C (P < 0.01). Group B animals had low SEA-induced IFN-γ levels and elevated IL-5 levels, although these were lower than group C. SEA-induced IL-10 was low in both groups A and B as compared to group C (P < 0.01). SWAP was less effective as an inducer of splenocyte cytokine production than SEA but both SWAP-induced IFN-γ and IL-5 were detected in groups A and C. SEA- and SWAP-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) titres were not significantly different between the three groups. Granuloma diameters were larger in group C (mean 297 ± 51.3 μm) as compared to groups A (174 ± 49 μm, P < 0.01) and B (247.5 ± 44 μm, P < 0.05). Taken together, these results demonstrate that granuloma size is reduced during a reinfection exposure compared with a primary infection. This reduction is associated with a T helper I response in mice exposed to a single large dose of cercariae in the primary infection and with a predominantly T helper 2 response in those infected with multiple small doses.