Background: Over half the world's population is at risk for viruses transmitted by Aedes mosquitoes, such as, dengue and Zika. The primary vector, Aedes aegypti, thrives in urban environments. Despite decades of effort, cases and the geographic range of Aedes-borne viruses (ABV) continue to expand. To date, there are no rigorously proven vector control interventions that prevent ABV diseases. Spatial repellents, a new option, are designed to decrease human exposure to ABV by releasing active ingredients into the air that disrupt mosquito-human contact. Methods: A parallel, cluster-randomized controlled trial was conducted in Iquitos, Peru to quantify the impact of a transfluthrin-based spatial repellent on ABV infection. From 2,907 households across 26 clusters (13 per arm), 1,578 participants were assessed for seroconversion (primary endpoint) by survival analysis. Incidence of acute disease was calculated among 16,683 participants (secondary endpoint). Bi-monthly adult mosquito collections were conducted to compare Ae. aegypti abundance, blood-fed capture rate and parity status through mixed effect difference-in-difference analyses. Results: The spatial repellent significantly reduced ABV infection by 34.1% (95% CI 6.9%, ∞); p = 0.0236, z=1.98). Aedes aegypti abundance and blood-fed capture rates were significantly reduced by 28.6% (95% CI 24.1%, ∞); z=-9.11) and 12.4% (95% CI 4.2%, ∞); z=-2.43), respectively. Conclusions: Our trial provides the first conclusive evidence of significant protective efficacy by any chemical vector control intervention, in this case a spatial repellent, to reduce the risk of ABV transmission. Results support vector control as a beneficial component to ABV disease prevention. Trial registration number:NCT03553277 (clinicaltrials.gov)