The meningeal worm (Parelaphostrongylus tenuis) is a nematode parasite that commonly infects white-tailed deer (Odocoileus virginianus; WTD) throughout the deciduous forest biome and deciduous-coniferous ecotone of eastern and central North America; the species is not known to occur west of the grassland biome of central North America. We used county-specific prevalence data to evaluate potential effects of landscape and climatologic factors on the spatial distribution of meningeal worm infection in South Dakota, US. Probability of infection increased 4-fold between eastern and western South Dakota and 1.3-fold for each 1-cm increase in summer precipitation. Sixty-three percent of WTD had only a single worm in the cranium. Expansion of meningeal worm infection across western South Dakota may be inherently low due to the combined effects of arid climate and potential attributes of the Missouri River that limit regional movements by infected WTD. Use of landscape genetic analyses to identify potential relationships between landscape features and population genetic structure of infected deer and parasites may contribute to a greater understanding of regional heterogeneity in meningeal worm infection rates across South Dakota, particularly in counties adjacent to the Missouri River. Future research evaluating heterogeneity in prevalence and intensity of infection between fawn and yearling deer, and the potential role of yearling male deer as dispersal agents of meningeal worms across the Missouri River, also is warranted.