A total of 44 samples of late Cenozoic (early Pliocene to Recent) nonmarine mollusks were obtained from 33 localities in the central and southern High Plains extending from central southern Nebraska through Kansas and Oklahoma to northwestern Texas. The water-insoluble fraction of residual shell-proteins or shell-peptides was isolated by decalcification and dialysis followed by filtration. Total protein-nitrogen of this fraction was determined by the micro-Kjeldahl method. Statistical analyses of protein-nitrogen content, expressed in μg of nitrogen per g of dry shell, indicate that: (1) Within the same Stratigraphic unit, shell protein-nitrogen content (SPN) is similar in related taxa (fresh-water mollusks as one group, and Succinea as another group) regardless of species difference and geographic location. (2) Within fresh-water mollusks or within Succinea, there is a consistent decrease in SPN value from Recent through Wisconsinan, Illinoian, Kansan, and Nebraskan to early Pliocene. (3) Within fresh-water mollusks or within Succinea, there is a statistically significant difference in SPN values between adjacent Stratigraphic units. From these data it is apparent that the SPN values are good Stratigraphic indicators for regional geologic correlation. The component of variation in SPN values that is attributable to the difference in the climatic conditions between adjacent geologic ages permits qualitative and quantitative interpretation of climatic conditions in the past. The qualitative interpretation of the climatic trend toward aridity in the late Cenozoic of the Great Plains made by the past workers is supported by the analyses of fossil shell-proteins.