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To determine if resistance/tolerance to the antischistosomal drug praziquantel (PZQ) is appearing in Egyptian villages within the Nile delta region, where it has been used extensively, we treated 1,607 infected villagers and observed that 321 required one additional treatment while 89 villagers required two additional treatments; 24 of the 89 were still not cured after a third dose of this drug. Eggs were isolated from fecal samples and serum was isolated from blood taken from seven villagers successfully treated after a single dose and from 14 villagers not successfully treated after two or three doses of PZQ. The eggs were used to establish infections in mice (isolates), which were then treated six weeks after infection with three different doses of PZQ. Serum was used to determine the concentration of PZQ in the infected humans. Three of the egg isolates from the 14 villagers that could not be treated with three doses of PZQ produced infections in mice that were statistically less responsive to PZQ when compared with isolates obtained from patients that were cured after a single dose of this drug. Pharmacokinetic parameters were the same in patients treated successfully after a single dose versus those not treated successfully following two or three doses, thus eliminating the possibility that poor cure rates among infected villagers was due to a decrease in PZQ bioavailability. From our data, approximately 1–2.4% of the villagers treated with PZQ could not be completely cured of their infection and three of every 1,000 treated villagers may harbor parasites that can tolerate high doses of PZQ. These results indicate that the extensive use of PZQ in the Nile delta region of Egypt has not resulted in a dramatic change in the efficacy of this drug. The isolation of schistosomes that are less susceptible to PZQ may be a warning signal that will require establishment of a monitoring system, similar to the one we have developed, to determine if the precentage of patients that cannot be cured by PZQ is increasing. Furthermore, if that percentage begins to increase over time, it will be critical to determine, by pharmacologic methods reported in this study, whether isolates obtained from uncured patients are becoming increasingly resistant to PZQ.