We examined the long-term efficacy of praziquantel against Schistosoma haematobium, the causative agent of urinary schistosomiasis, during a school-based treatment program in the Msambweni area of Coast Province, Kenya, where the disease is highly endemic. Our results, derived from treating 4,031 of 7,641 children from 1984 to 1993, indicate substantial year-to- year variation in drug efficacy. However, the pattern of this variation was not consistent with primary or progressive emergence of praziquantel resistance. Mathematical modeling indicated that, at current treatment rates, praziquantel resistance will likely take 10 or more years to emerge.