For nearly 500 years, scholars have argued about the origin and antiquity of syphilis. Did Columbus bring the disease from the New World to the Old World? Or did syphilis exist in the Old World before 1493? Here, we evaluate all 54 published reports of pre-Columbian, Old World treponemal disease using a standardized, systematic approach. The certainty of diagnosis and dating of each case is considered, and novel information pertinent to the dating of these cases, including radiocarbon dates, is presented. Among the reports, we did not find a single case of Old World treponemal disease that has both a certain diagnosis and a secure pre-Columbian date. We also demonstrate that many of the reports use nonspecific indicators to diagnose treponemal disease, do not provide adequate information about the methods used to date specimens, and do not include high-quality photographs of the lesions of interest. Thus, despite an increasing number of published reports of pre-Columbian treponemal infection, it appears that solid evidence supporting an Old World origin for the disease remains absent. Yrbk Phys Anthropol 54:99–133, 2011. © 2011 Wiley Periodicals, Inc.