From its establishment by royal decree in 1610 until its abolition in 1821, the Inquisition tribunal of Cartagena de Indias sought to stamp out heresy and maintain Catholic orthodoxy among the inhabitants of the territory of New Granada. This thesis examines the activities of the tribunal during the first half of the seventeenth century, specifically as they relate to its persecution of the crypto-Jews under its jurisdiction. While the surviving evidence demonstrates a significant crypto-Jewish presence in Cartagena in the 1600s, and even though the authority of this tribunal extended far beyond its immediate surroundings, very few crypto-Jews were ever prosecuted by this court during this time. This thesis explores the social, economic and political dynamics explaining a change in policy that led to a rise in the number of Inquisition trials against the crypto-Jewish population in the first half of the seventeenth century. This thesis argues that Spanish imperial politics coupled with socio-economic factors inherent in the colonial system, explains why inquisitorial persecution increased in this period.