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This article explores the prominent role that so-called middle powers have played in constructing the Proliferation Security Initiative (PSI) as an innovative framework for multinational cooperation, in this case designed to counter trafficking related to weapons of mass destruction proliferation. It seeks thereby to contribute to a better theoretical understanding of the international role and foreign policy behavior of this class of state actor. Because the preponderance of middle power scholarship is either broadly conceptual or focuses narrowly on national-level case studies, an examination of middle power involvement in a particular global initiative represents a potentially important theory-building contribution. Drawing on a critical review of the literature on middle powers, and an explication of PSI through the analytic prism of middle power participation, the study proposes that PSI affords novel insights about—and plausibly a template auguring new opportunities for—middle power activism, collaboration, and influence in global security affairs.