Successful therapy with praziquantel in schistosomiasis is dependent on a normal host immune system, i.e. the recognition of parasite antigen, to be effective in eradicating the parasite. Levamisole, a nonspecific immunomodulator, has been hypothesised to normalise deficient cell-mediated immunity. The aim of this study was to investigate the effect of levamisole on the immune response seen after presumed curative doses of praziquantel. After ethical approval, 29 male volunteers infected with Schistosoma haematobium were recruited and randomised to receive orally either (a) levamisole 5 mg/kg for 2 consecutive days, plus praziquantel 40 mg/kg as a single dose, (b) levamisole 5 mg/kg for 2 days, or (c) praziquantel 40 mg/kg as a single dose. Blood samples were collected on day 0 and again 3 months later for differential counts and specific IgG and IgE to whole-worm-antigen, as well as for the detection of eosinophil cationic protein (ECP). Levamisole treatment alone resulted in a significant drop in circulating eosinophil counts, i.e. a median (95% confidence interval) drop of 6.0 (1;7)%. Eosinophil counts did not change significantly after praziquantel therapy alone. ECP values were significantly reduced with levamisole alone and praziquantel alone, i.e. respective median (95% confidence interval) drops of 33.58 (18.94; 55.9) and 16.54 (3.6; 33.5) microg/L (p < 0.05). The group receiving combination therapy demonstrated significant increases in specific IgG values (p = 0.02) with no decline in ECP levels and eosinophil counts compared with baseline values. Levamisole alone had no effect on egg counts. In conclusion, levamisole inhibited circulating eosinophils and eosinophil activation when given alone, but caused immune stimulation when combined with praziquantel. The exact mechanism of action still needs to be determined.