This article explores the living conditions and specifically the possible etiologies of subperiosteal reactions among those seafarers who did not survive Christopher Columbus' second voyage to the Americas and died at La Isabela, the first permanent European settlement in the New World, which is located in the present-day Dominican Republic. The town was founded in 1494 by Christopher Columbus (1451–1506) and occupied for only 4 years. This study analyses the macroscopic and histological evidence of the skeletal series excavated from this contact cemetery, which is presently curated at the Museo del Hombre Dominicano. Twenty of the 27 systematically scored individuals reveal subperiosteal bone accretions, and in at least 15 individuals, these accretions appear bilaterally. The morphology, distribution and healing stages of the majority of these lesions provide new, direct evidence suggesting severe adult scurvy, a condition caused by sustained vitamin C deprivation, which was common among seafarers before the 18th century. The historical context surrounding the individuals' death at the European contact settlement and the conditions and duration of Christopher Columbus' second transatlantic voyage to the New World represent key elements in the interpretation of these lesions. In this case, the evidence also corroborates the known failure of Columbus' crew to exploit the locally available foods rich in vitamin C. Scurvy probably contributed significantly to the outbreak of sickness and collective death within the first months of La Isabela's settlement, an aspect that inflects the current discussion about the degree of virulence of New World infections that decimated the European newcomers, who we conclude to have been already debilitated and exhausted by scurvy and general malnutrition. Copyright © 2014 John Wiley & Sons, Ltd.