International Relations theory has recently turned its attention to the study of comparative regionalism in economics and security. As part of this new research agenda, this article explores what we might learn from the Southern Cone's experience with denuclearization that might be applicable to the Middle East. The two regions differ with respect to security dilemmas, military capabilities and doctrines, and the prior availability of a cooperative regional institutional infrastructure. Yet two aspects of the Southern Cone process seem potentially relevant to other regions. The first relates to improving our understanding of the appropriate domestic political conditions that underpin denuclearization. In particular, the nature of domestic coalitions and of their respective approaches to the global economy and political institutions deserve far more serious consideration than they have gained thus far. The second relates to the nature of the regional denuclearization regime initially fashioned in the Southern Cone, which set an international precedent. A regionally-based system of mutual inspections could help remove some of the most intractable barriers to a future Middle East free of weapons of mass destruction.