Conodont apatite δ18OV-SMOW values from Middle though Upper Pennsylvanian (Desmoinesian–Missourian) laminated, marine black shale units within cyclic deposits of intercalated terrestrial and marine strata (cyclothems) from the Illinois Basin (United States) were measured in order to evaluate their utility as a proxy for changes in the oxygen isotopic composition of the epicontinental Late Pennsylvanian Midcontinent Sea (LPMS). The average δ18OV-SMOW values of well-preserved monogeneric (Idiognathodus) separates of conodont apatite from 12 lithologic units representing nine cyclothems range from 17.0‰ to 20.1‰ and average 19.0‰ ± 0.4‰ (1σ). Within the limits of analytical uncertainty of stable isotope measurements, the stratigraphic distribution of conodont apatite δ18O values is nontrending; particularly, there is no significant shift in δ18O values across the Desmoinesian–Missourian boundary, a period that has been interpreted to preserve a shift toward a warmer climate, increased seasonality, and shorter periods of wet conditions in the terrestrial record. Conodont apatite δ18O values from stratigraphically equivalent black shale members across the Illinois Basin vary up to 2.6‰, which is nearly equivalent to the observed stratigraphic range of conodont apatite δ18O values, and suggests differences in local (basin-scale) seawater δ18O values affected the conodont apatite δ18O values. Within analytical uncertainty, conodont apatite δ18O values from the Illinois Basin and Midcontinent Basin (United States) are indistinguishable, suggesting a component of overarching broader regional to global controls on seawater δ18O values. Nevertheless, if the large variability observed in stratigraphically equivalent black shale members in the Illinois Basin is attributed to regional factors, these results indicate caution should be used when attempting to interpret temporal shifts from single aliquots of conodonts in epicontinental settings.