Purpose: Praziquantel (PZQ) is the preferred drug for schistomiasis treatment because of its safety. As PZQ is used for mass drug administration (MDA) in schistosomiasis endemic areas, the effectiveness of the drug, used solely for decades, should be continuously monitored to detect drug resistance. We aimed to assess the effectiveness of PZQ to cure Schistosoma mansoni infection and to reduce the intensity of infection in an endemic area by estimating the cure rate (CR), egg reduction rate (ERR), and comparing these estimates to the levels recommended by the World Health Organization (WHO). Methods: A total of 342 children aged 5–15 years living in Kafr-El-Sheikh were screened for S. mansoni infection. Stool samples were examined microscopically using Kato–Katz (KK) technique. Among the screened children, 106 children had S. mansoni ova in stool, 100 of them received the first dose of PZQ (40 mg/kg). Four weeks later, 96 of 100 children received the second dose of PZQ. Stool samples, collected 4 weeks after each dose of PZQ, were examined using KK. The effectiveness of PZQ was assessed based on ERR and CR. Results: CR after the first dose of PZQ was 66.7%, increased to 79.12% after second dose (X2 = 3.05, P = 0.08). Median egg count before treatment was 30.00 (6.00–744), that significantly decreased after two doses of PZQ to 0.00 (0.00–221.33) (Z = 8.29, P = 0.001). Children aged 10–15 years showed higher CR (91.3%) than those aged 5–9 years (OR = 5.25, CI 1.58–17.40). Conclusions: PZQ is still an effective agent against S. mansoni in endemic areas, achieving a high CR and ERR with predominantly low intensity of infection. Age is a main predictor of response to PZQ. [ABSTRACT FROM AUTHOR]