New tree-ring records of ring-width from remnant preserved wood are analyzed to extend the record of reconstructed annual flows of the Colorado River at Lee Ferry into the Medieval Climate Anomaly, when epic droughts are hypothesized from other paleoclimatic evidence to have affected various parts of western North America. The most extreme low-frequency feature of the new reconstruction, covering A.D. 762-2005, is a hydrologic drought in the mid-1100s. The drought is characterized by a decrease of more than 15% in mean annual flow averaged over 25 years, and by the absence of high annual flows over a longer period of about six decades. The drought is consistent in timing with dry conditions inferred from tree-ring data in the Great Basin and Colorado Plateau, but regional differences in intensity emphasize the importance of basin-specific paleoclimatic data in quantifying likely effects of drought on water supply.