A sustained mid-nineteenth-century drought in the western Great Plains has been indicated by a tree-ring analysis of trees flanking the western Great Plains, and in tree-ring reconstructions of drought and streamflow for eastern Colorado and the Colorado Front Range. The development of new tree-ring chronologies for the western Great Plains, in combination with existing chronologies, now enables a more detailed assessment of the spatial and temporal characteristics of this drought. The analysis of a set of drought-sensitive tree-ring chronologies ranging from the northwestern Great Plains to central New Mexico indicates a core area of drought from south-central Wyoming to northeastern New Mexico for the years 1845-56. Drought was particularly severe in the years 1845-48, 1851, and 1854-56, contracting and affecting smaller regions in intervening years. The impact of this drought on natural ecosystems and human activities is difficult to gauge because of the paucity of historical documents and the confounding effects of land use changes occurring over the same period. However, it is probable that this drought played a role in the decimation of bison herds in the second half of the nineteenth century. Were it to occur today, this relatively small but persistent drought would have significant impacts on the Colorado Front Range metropolitan area and the agricultural regions of eastern Colorado.