Abstract Background Endemic coronaviruses (“CoVs”) OC43, HKU1, NL63 and 229E are “common cold viruses” related to SARS-CoV-2, but their natural histories are poorly understood. We documented endemic CoV infections in a prospective cohort of US infants and children to determine the extent to which natural infection protects against subsequent homotypic and heterotypic endemic CoV infections and SARS-CoV-2 infections. Methods Cincinnati mother-child pairs were enrolled in the third trimester of pregnancy in 2017-18 and children were followed from birth to 4 years with weekly collection of mid-turbinate nasal swabs. Blood was collected at 6 weeks; 6, 12, 18, 24 months; and annually thereafter. Mothers reported on socio demographics, risk factors, and the child’s weekly symptoms. Medical visits were documented from pediatric care providers. CoV infections were followed for the first 4 years of life (focusing on the most compliant subset of 116 children having >70% weekly sample collection). Infections were identified through nasal swabs tested using a RT-PCR multiplex pathogen panel, and by serum IgG responses using a validated kit at CDC and interpreted using classification and regression tree (CART) analysis. Results We detected 398 endemic CoV infections over 317.5 child-years of follow-up (1.1 infections/child-year). Endemic beta-coronaviruses, OC43 and HKU1, were associated with statistically significant homotypic protection (77% and 84%, respectively) after a single infection. Similarly protective homotypic associations (73%) were elicited by NL63, the dominant alpha-coronavirus, after two infections. 229E infections were uncommon. No heterotypic protective association was found for any of the endemic CoVs or for SARS-CoV-2 infections from June 2020 to Nov 2021. The majority of endemic CoVs and SARS-CoV-2 infections were asymptomatic, but this proportion varied by CoV strain. Symptomatic infections were mild for all CoV strains with no hospitalizations. Conclusion Natural infection resulted in homotypic immunity but not heterotypic immunity against other CoVs to the 4th birthday. Children were not protected against SARS-CoV-2 by prior endemic CoV infections. CoV infections in these young children were largely asymptomatic or mild. Disclosures Elizabeth P. Schlaudecker, MD, MPH, Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Mary A. Staat, MD, MPH, CDC: Grant/Research Support|Cepheid: Grant/Research Support|Merck: Grant/Research Support|NIH: Grant/Research Support|Pfizer: Grant/Research Support|Up-To-Date: Honoraria