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Hypertrophic osteoarthropathy is one of the earliest recognized disease entities in the history of medicine. It has a peculiar periosteal proliferation distinctive from other bone diseases. In its advanced stage, it leaves an indelible mark on the skeleton. It has been recently shown that digital clubbing is accompanied by a bone remodeling process of the underlying phalanges. Thus, theoretically, this entity can be recognized in ancient human skeletal remains. We studied part of the collection of skeletal remains from pre-Hispanic Mesoamerica preserved at the National Museum of Anthropology of Mexico City. We examined 1000 specimens and found 2 skeletons with widespread, bilateral, symmetric periosteal proliferation of the tubular bones in addition to the bone remodeling changes of the distal phalanges. One of the specimens was from the Formative period (2000 B.C. to 100 A.D.). We conclude that hypertrophic osteoarthropathy can be recognized in ancient human skeletal remains and that this disease was present in Mesoamerica near the time of the original description of clubbing by Hippocrates about 2500 years ago.