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Background: Malaria elimination using current tools has stalled in many areas. Ivermectin (IVM) is a broad-antiparasitic drug and mosquitocide and has been proposed as a tool for accelerating progress towards malaria elimination. Under laboratory conditions, IVM has been shown to reduce the survival of adult Anopheles populations that have fed on IVM-treated mammals. Treating cattle with IVM has been proposed as an important contribution to malaria vector management, however, the impacts of IVM in this One Health use case have been untested in field trials in Southeast Asia. Methods: Through a randomized village-based trial, this study quantified the effect of IVM-treated cattle on anopheline populations in treated vs. untreated villages in Central Vietnam. Local zebu cattle in six rural villages were included in this study. In three villages, cattle were treated with IVM at established veterinary dosages, and in three additional villages cattle were left as untreated controls. For the main study outcome, the mosquito populations in all villages were sampled using cattle-baited traps for six nights before, and six nights after a 2-day treatment IVM-administration (intervention) period. Anopheline species were characterized using taxonomic keys. The impact of the intervention was analyzed using a difference-in-differences (DID) approach with generalized estimating equations (with negative binomial distribution and robust errors). This intervention was powered to detect a 50% reduction in total nightly Anopheles spp. vector catches from cattle-baited traps. Given the unusual diversity in anopheline populations, exploratory analyses examined taxon-level differences in the ecological population diversity. Results: Across the treated villages, 1,112 of 1,527 censused cows (73% overall; range 67% to 83%) were treated with IVM. In both control and treated villages, there was a 30% to 40% decrease in total anophelines captured in the post-intervention period as compared to the pre-intervention period. In the control villages, there were 1,873 captured pre-intervention and 1,079 captured during the post-intervention period. In the treated villages, there were 1,594 captured pre-intervention, and 1,101 captured during the post-intervention period. The difference in differences model analysis comparing total captures between arms was not statistically significant (p = 0.61). Secondary outcomes of vector population diversity found that in three villages (one control and two treatment) Brillouin's index increased, and in three villages (two control and one treatment) Brillouin's index decreased. When examining biodiversity by trapping-night, there were no clear trends in treated or untreated vector populations. Additionally, there were no clear trends when examining the components of biodiversity: richness and evenness. Conclusions: The ability of this study to quantify the impacts of IVM treatment was limited due to unexpectedly large spatiotemporal variability in trapping rates; an area-wide decrease in trapping counts across all six villages post-intervention; and potential spillover effects. However, this study provides important data to directly inform future studies in the GMS and beyond for IVM-based vector control. Author summary: Malaria incidence in Vietnam has substantially declined in the last decade, however, current prevention strategies may be insufficient to achieve national elimination goals. A proposed tool for use as a mosquitocide is zooprophylaxis-aided ivermectin-based elimination (i.e., treating cattle with ivermectin to kill feeding mosquitoes). Ivermectin (IVM) is an inexpensive helminthicide and is safe for use in mammals. In laboratory studies, mosquitoes feeding on IVM-treated cattle have increased mortality compared to controls. Presented here is a randomized village-based trial to determine whether IVM treatment can reduce the number of captured mosquitoes. Six villages in Central Vietnam were randomly assigned to either receive IVM treatment or remain a control. Mosquitoes in each village were captured for six trap nights, followed by treatment in three villages, followed by trapping for an additional six nights. A difference-in-differences model did not show any statistically significant differences in capture rates between the treated and control villages. Factors including the amount of circulating IVM in the cattle population, crossover of mosquito populations, and differential feeding habits may have affected captures. A total of 18 species were identified using dichotomous keys. In post hoc analyses, no clear trends were observed in the anopheline populations after IVM treatment, as measured by ecological diversity metrics. Future studies should include additional villages, greater control of cattle movements, and consider potential vector movements. [ABSTRACT FROM AUTHOR]