Schistosomiasis is a chronic debilitating disease that continues to threaten millions of people, and to be the 2nd major parasitic disease worldwide after malaria in term of morbidity, mortality, and prevalence. The treatment and control of human schistosomiasis rely on a single drug, praziquantel (PZQ), that effectively kills adult schistosomes but lacks efficacy against schistosomulae (juvenile schistosomes) a fact that explains low observed cure rates of schistosomiasis. The antimalarial drug mefloquine (MFQ) proved to have interesting anti-schistosomal properties against varies stages of Schistosoma in vivo.The present study was carried out to evaluate the anti-schistosomal activity of a single oral dose (400 mg/kg) of MFQ in different groups of laboratory bred swiss albino mice experimentally infected with S. mansoni cercariae (Egyptian strain) as a chemoprophylactic, chemotherapeutic agent and to induce resistance to re-infection. Reduction in worm burden, parasite fecundity (oogram pattern and tissue egg load) and disease burden (number, size and cellular components of the bilharzial hepatic granuloma) were used as a drug targets to assess its anti-schistosomal activity.Single dose of MFQ showed a statistically significant chemoprophylactic effect through reduction of worm burden, tissue egg load, hepatic granulomata size and numbers and tegumental changes when administrated one day pre-infection and a statistically significant chemotherapeutic effect through induction of complete killing of all S. mansoni worms when administrated on the day 21 post-infection with no eggs or granulomas in tissues and a marked reduction of worm burden, tissue egg load, hepatic granuloma size and numbers and severe tegumental changes when administrated 6 weeks post-infection. Also, MFQ significantly influenced resistance to re-infection compared to PZQ.This model needs to be replicated in human individuals, MFQ as an alternative to PZQ with significant chemoprophylactic and chemotherapeutic efficacy and significant induction of resistance to re-infection with schistosomiasis mansoni may be a promising treatment regimen as a strategy for S. mansoni prevention and control programs that prevent treatment failures especially in areas of repeated infections.