Schistosoma mansoni is one of the major causes of schistosomiasis prevalent in tropical and subtropical areas, especially in poor communities. It is estimated that at least 90% of those requiring treatment for schistosomiasis live in Africa. The primary control strategy employed for schistosomiasis is mass drug administration (MDA).The aim is to reduce disease through treatments with a single lower dose of Ro 15-9268 as a new antischistosomal drug. In the present search, the efficacy of Ro 15-9268 was studied in mice using a dose of 12.5 mg/kg of body weight (b.wt.) against an Egyptian strain of S. mansoni. This was carried out at 2 days and 3, 4, and 6 weeks post-cercarial exposure of mice. The criteria used were the worm load, oogram pattern and number of ova in the liver and intestine, hepatic enzyme activity, and liver histopathology. The tested agent has led to a significant reduction in worm burden (89.80%) in liver and portomesenteric veins concurrent with a hepatic shift at the second week posttreatment followed by a complete disappearance of worms, 4 weeks postmedication. The oogram of infected animals treated revealed an increased number of dead ova 2 days posttreatment and complete absence of immature and mature ova 2 weeks later. The hepatic and intestinal egg counts significantly declined by about 96 and 98%, respectively, 6 weeks after treatment, and the fecal egg count completely disappeared from stool 4 weeks after medication. The hepatic histopathological changes were improved, ova were markedly degenerated, and worms showed fragmentation and degeneration after drug administration. In conclusion, when Ro 15-9268 was administered to mice infected with the Egyptian strain of S. mansoni, at a low dose level (12.5 mg/kg b.wt.), encouraging results were obtained. The drug showed high efficacy against schistosomal worms as well as histopathological inflammatory changes.