INTRODUCTION: Topical atropine eye drops at low concentrations have been shown to slow myopia progression in East Asian studies. This study explored the effect of atropine 0.01% eye drops on controlling myopia progression in a multiethnic cohort of children in the USA. METHODS: A multicenter retrospective case-control study (n = 198) quantified the effect of adding nightly atropine 0.01% eye drops to treatment as usual on the progression of childhood (ages 6-15 years) myopia. Cases included all children treated with atropine for at least 1 year. Controls were matched to cases on both age (± 6 months) and baseline spherical equivalent refraction (SER) (± 0.50 diopters, D) at treatment initiation. The primary endpoint was the average SER myopia progression after 1, 1.5, and 2 years of therapy. A secondary outcome was the percentage of subjects with a clinically significant worsening of myopia, defined as a greater than - 0.75 D SER increase in myopia. RESULTS: The average baseline SERs for the atropine (n = 100) and control (n = 98) groups were similar (- 3.1 ± 1.9 D and - 2.8 ± 1.6 D, respectively) (p = 0.23). The average SER increase from baseline was significantly less for the atropine group than the control group at year 1 (- 0.2 ± 0.8 D compared with - 0.6 ± 0.4 D, p < 0.001) and at year 2 (- 0.3 ± 1.1 D compared with - 1.2 ± 0.7 D, p < 0.001). Secondary analysis at year 2 revealed that 80% of the control group vs. 37% of the atropine group experienced clinically significant worsening myopia of at least - 0.75 D (p < 0.001). There were no major safety issues reported in either group. CONCLUSION: Similar to results reported in Asia, atropine 0.01% eye drops significantly reduced myopia progression in a cohort of US children over 2 years of treatment. FUNDING: Nevakar, Inc. Plain language summary available for this article.