Droughts in pre-Columbian Mesoamerica caused significant societal disruptions during the Late Classic and Post-Classic Periods. While the primary causes of these droughts are still debated, it has been speculated that they may be linked to extensive deforestation associated with high population densities during these intervals. Here we show that pre-Columbian deforestation would have biased the climate in Mesoamerica towards a drier mean state, amplifying drought in the region. In climate model simulations using a pre-Columbian land cover reconstruction, annual precipitation decreases by 5%-15% throughout southern Mexico and the Yucatan compared to simulations using either natural forest cover or forest regrowth associated with population declines after 1500 C. E. These changes are driven primarily by large reductions (10%-20%) in precipitation during the late summer wet season (August-September). When compared to precipitation changes estimated to have occurred during the Maya collapse, our results suggest that deforestation could account for up to sixty percent of the mean drying during this interval. Many regions previously deforested in the pre-Columbian era are now under dense forest cover, indicating potential future climate impacts should tropical deforestation of these areas accelerate. Citation: Cook, B. I., K. J. Anchukaitis, J. O. Kaplan, M. J. Puma, M. Kelley, and D. Gueyffier (2012), Pre-Columbian deforestation as an amplifier of drought in Mesoamerica, Geophys. Res. Lett., 39, L16706, doi:10.1029/2012GL052565.