The Spanish Conquest of the Americas opened up the doors to new trade routes within and beyond Europe. The increasing circulation of capitals rested on partnerships (societates), census contracts, triple contracts, titles to interest (interesse) and other financial operations which potentially conflicted with the usury prohibition. Domingo de Soto (1494-1560), Martín de Azpilcueta (Dr. Navarrus, 1491-1586), and other leading theologians of the School of Salamanca discussed these operations starting from the teachings of Thomas Aquinas. They sought to reconcile the merchants’ private interest with the need to safeguard benefits for the community and the salvation of the souls. On the other side of Europe, in Northern Germany, Martin Luther (1483-1546), Philip Melanchthon (1497-1560) and other theologians were also wrestling with conflicts between business operations and the usury prohibition. Contrary to the scholastics, the Lutherans started from biblical exegesis and the two kingdoms doctrine. This paper offers a comparative view of the Scholastic and Lutheran analysis of lending at interest, with special focus on the five percent contract, a popular financial operation which guaranteed revenues of 5% of the invested sum. The aim is to show how different theological underpinnings generated different answers to moral/legal issues related to business, but also important points of contact. After a brief introduction, section 1 contextualizes the sources in the Catholic and the Lutheran world. Section 2 summarizes the standard guidelines proposed by Soto, Azpilcueta and other Spanish Scholastics to face moral/legal questions on business and the five percent contract. Section 3 offers an overview of Luther’s and Melanchthon’s main attitudes towards business and their opinion on the five per cent contract. It also investigates how famous Lutheran jurists like Johannes Scheidewin (1519-1568), Matthaeus Wesenbeck (1531-1586) and Jakob Thoming (1524-1576) applied their theories. Section 4 compares the Catholic and Lutheran teachings and presents some concluding remarks.