The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA reductase) plays an important role in regulating egg production in the human parasitic trematode Schistosoma mansoni. Infected mice treated with a low dose of mevinolin, an inhibitor of this enzyme, stopped egg production by the parasite and blocked the pathology associated with the infection. As an extension of this work, we exposed adult and developing schistosomes to higher doses of mevinolin for an extended period of time and observed the following: administration of 0.2% mevinolin in the diet of infected mice for 14 days resulted in 96-100% elimination of adult parasites. Administration of the same dose for 2 days before, and for 15 days after infection, resulted in 93-96% reduction of adult parasites. Co-administration of mevinolin with 0.5% mevalonate, but not 0.5% cholesterol, blocked the antischistosomal activity of mevinolin. We monitored schistosomal and mouse liver HMG-CoA reductase activity during the course of treatment and observed that HMG-CoA reductase activity was elevated in the liver but significantly reduced in the parasite. In vitro incubation of paired schistosomes with mevinolin, for up to 11 days, resulted in a dose- and time-dependent reduction of parasite motility and lactate production with eventual death. These in vitro effects were no evident when mevalonate was added to the culture system in place of, or in addition to, mevinolin. Collectively, the evidence suggests that mevalonate and/or metabolite not only plays a vital role in schistosome egg production, but is vital for survival of the parasite.