BackgroundChagas disease, a vector-borne parasitic disease caused byTrypanosoma cruzi, affects millions in the Americas. Dogs are important reservoirs of the parasite. Under laboratory conditions, canine treatment with the systemic insecticide fluralaner demonstrated efficacy in killingTriatoma infestansandT.brasiliensis,T.cruzivectors, when they feed on dogs. This form of pest control is called xenointoxication. However,T.cruzican also be transmitted orally when mammals ingest infected bugs, so there is potential for dogs to become infected upon consuming infected bugs killed by the treatment. Xenointoxication thereby has two contrasting effects on dogs: decreasing the number of insects feeding on the dogs but increasing opportunities for exposure toT.cruzivia oral transmission to dogs ingesting infected insects.ObjectiveExamine the potential for increased infection rates ofT.cruziin dogs following xenointoxication.Design/MethodsWe built a deterministic mathematical model, based on the Ross-MacDonald malaria model, to investigate the net effect of fluralaner treatment on the prevalence ofT.cruziinfection in dogs in different epidemiologic scenarios. We drew upon published data on the change in percentage of bugs killed that fed on treated dogs over days post treatment. Parameters were adjusted to mimic three scenarios ofT.cruzitransmission: high and low disease prevalence and domestic vectors, and low disease prevalence and sylvatic vectors.ResultsIn regions with high endemic disease prevalence in dogs and domestic vectors, prevalence of infected dogs initially increases but subsequently declines before eventually rising back to the initial equilibrium following one fluralaner treatment. In regions of low prevalence and domestic or sylvatic vectors, however, treatment seems to be detrimental. In these regions our models suggest a potential for a rise in dog prevalence, due to oral transmission from dead infected bugs.ConclusionXenointoxication could be a beneficial and novel One Health intervention in regions with high prevalence ofT.cruziand domestic vectors. In regions with low prevalence and domestic or sylvatic vectors, there is potential harm. Field trials should be carefully designed to closely follow treated dogs and include early stopping rules if incidence among treated dogs exceeds that of controls.