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We sought to identify counties in the northeastern United States where the incidence of infant botulism (IB) is elevated compared to the nationwide incidence and to assess associations with soil type at the case residence. IB cases were identified through the distribution of the orphan drug Human Botulism Immune Globulin Intravenous for treatment of IB by state and national surveillance systems and were subsequently confirmed by laboratory testing. IB incidence by county was calculated as the number of IB cases divided by the number of live births in the county from 2000 to 2019. Cases were spatially mapped and assigned to soil types using the US Department of Agriculture’s online soils database. Possible association with soil type was evaluated with the Chi-squared test. We identified a rectangular area consisting of 17 contiguous counties in Delaware, Maryland, New Jersey, New York, and Pennsylvania, approximately 80 km by 250 km, in which the 20-year incidence of IB was nearly seven times greater than that of the remaining counties in those five states. Within this area, case residences were strongly associated with certain soil types (P ≤ 0.003). From 2000 to 2019, IB occurred with disproportionate incidence in a rectangular area encompassing the lower Delaware and Raritan River Valley and parts of five adjacent states. Further investigation of the soils in counties from this area could assess whether C. botulinum is more prevalent in certain soil types and whether isolation of C. botulinum is more common in counties with higher IB incidence. IMPORTANCE Infant botulism occurs more frequently in 17 counties within and adjacent to the Delaware and Raritan River watersheds. This study should alert physicians and pediatricians in the area to the higher likelihood of encountering cases of this otherwise rare disease that manifests with constipation, poor feeding, loss of head control, weak suck/cry, generalized weakness, and descending bilateral paralysis. [ABSTRACT FROM AUTHOR]