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Study Objectives: Cultural sleep practices and COVID-19 mitigation strategies vary worldwide. The sleep of infants and toddlers during the COVID-19 pandemic in the United States is understudied., Methods: Caregivers of children aged < 3 years responded to a cross-sectional survey during 2020 (divided into quarters, with the year quarter 1 being largely prelockdown). We assessed the global effect of year quarter on parent-reported total sleep time (hours) and sleep onset latency (hours) using an analysis of variance. We used multivariable linear regression to assess the adjusted effect of year quarter on total sleep time, sleep onset latency, and parental frustration. We used logistic regression to assess the adjusted effect of year quarter on nap consistency., Results: Of 594 children, the mean age was 18.5 ± 9.7 months; 52% were female. In the adjusted analyses, the reference categories were as follows: quarter 1 (year quarter), ≤ 6 months (age category), and < $25,000 (annual household income). Total sleep time was associated with age category (ages 12 to ≤ 24 months: β = -2.86; P  = .0004; ages 24 to ≤ 36 months: β = -3.25; P  < .0001) and maternal age (β = -0.04; P  = .05). Sleep onset latency was associated with year quarter (year quarter 3: β = 0.16; P  = .04), age category (ages 24 to ≤ 36 months: β = 0.28; P  < .0001), annual household income ($100,000-$150,000: β = -0.15; P  = .03; > $150,000: β = -0.19; P  = .01), and lack of room-sharing (β = -0.09; P  = .05). Parental frustration with sleep increased with age (all P  < .05) and lack of room-sharing ( P  = .01). The effect of lack of room-sharing on nap consistency approached significance (adjusted odds ratio, 1.88; 95% confidence interval, 0.95-3.72)., Conclusions: Social factors such as lower household income and room-sharing affected the sleep of U.S. infants and toddlers as opposed to the COVID-19 lockdown itself., Citation: Gupta G, O'Brien LM, Dang LT, Shellhaas RA. Sleep of infants and toddlers during 12 months of the COVID-19 pandemic in the midwestern United States. J Clin Sleep Med. 2022;18(5):1225-1234., (© 2022 American Academy of Sleep Medicine.)