Data sharing and interoperability aspects of Europol’s information systems outside the EU are particularly problematic because of the difficulty of ensuring that adequate legal safeguards are complied with in partner third countries and international organizations. At the same time, the way in which the ongoing interoperability initiatives regarding the Area of Freedom, Security and Justice (AFSJ) databases may influence Europol’s international cooperation raises arguably a set of new legal and practical questions that require urgent consideration. This article examines these issues by connecting the Europol-specific legal framework and international practice to the recently adopted AFSJ interoperability regulations as well as to the EU broader data protection framework. It looks more specifically at the balance between data protection/fundamental rights and operational effectiveness throughout Europol’s legal framework and practice of international cooperation and examines the implications of interoperability of AFSJ databases on this. On the one hand, interoperability of AFSJ databases is likely to boost Europol as an information hub through extended personal data collection and data processing possibilities, thereby making the Agency more attractive to international partners. On the other hand, the possibility to transfer such data outside the EU requires strong and effective safeguards from a data protection perspective. The article tentatively concludes that Europol’s current legal and practical framework for international cooperation seems to tilt the balance on the side of operational effectiveness to the detriment of data protection and fundamental rights, and that the new possibilities offered by the interoperability of AFSJ databases will further enhance this trend.