The Asian tapeworm Bothriocephalus achelognathii is an intestinal fish parasite that is nonnative to but widespread throughout the southwestern United States. Praziquantel is an anthelminthic drug commonly used to treat fish for Asian tapeworm; however, it does not kill tapeworm eggs, so the water in ponds used for fish rearing must be exchanged after treatment. Our objective was to determine whether a system containing both an intermediate copepod host and a definitive fish host for Asian tapeworm could be treated without exchanging the water by using a follow-up treatment for any tapeworms that developed from eggs released before or during the first treatment. Here, we have described a new praziquantel treatment regimen to control Asian tapeworm infections in freshwater-reared fish. To evaluate the efficacy of this regimen, we stocked 50 red shiners Cyprinella lutrensis and an intermediate copepod host, Cyclops vernalis, into each of six pond mesocosms containing artificial macrophytes, sand, and gravel to simulate natural pools and provide suitable substrate for the copepod's life history. The test fish population had been naturally infected with B. achelognathii and had an initial infection prevalence of 14% and an infection intensity of 2.14 ± 2.19 (mean ± SD) worms per fish. Three mesocosms were treated twice, each with 2.5 mg/L praziquantel; 19 d passed between treatments to allow for possible reinfection to occur. After a 2.5-month posttreatment period to allow any remaining tapeworms to reestablish themselves, we killed and dissected all of the remaining fish. No worms were found in treated fish; however, the control group had an infection prevalence of 18 ± 6% and an infection intensity of 3.45 ± 2.1 worms per fish. Based on these results, we concluded that the praziquantel treatment regime administered was efficacious and suggest testing it on a larger scale. We caution that praziquantel has not been approved by the U.S. Food and Drug Administration for use on fish but can be used legally in some situations.