Control of schistosomiasis would be greatly improved by the development of a vaccine, which could be combined with chemotherapy. The current study evaluated the potential effect of soluble egg antigens (SEA) associated with or without PZQ in Schistosoma mansoni challenged mice through parasitological, histopathological and serological studies. Sixty Swiss albino female mice divided into 5 groups (12 mice each); each group was subdivided into 2 groups (6 mice each) according initial and challenged infections. Mice were sacrificed by rapid decapitation 8 weeks post initial and challenge infections for assessment. The current results showed marked reduction of egg counts per gram stool, worm burden, granuloma number and size in combined SEA and PZQ group. Also, significant increase in serum IL-12 & INF-γ, plus marked decrease in serum IL-4 during initial and challenged infections. The role of PZQ alone was mainly during primary infection and had no role in reinfection, whereas, SEA alone was effective during challenged one. In conclusion, from the obtained results of the current study the combination of SEA & PZQ was as a possible potent and promising prophylactic treatment for schistosomiasis especially during re-infection in endemic areas. This prophylactic effect was significantly greater than those observed in the single drug treatment or vaccine used.