In the arena of international trade, multiple levels of governments (ranging from national to supranational) play an important role in regulating and controlling cross-border trade activities. Recently, they have also become powerful players in influencing decisions about inter-organizational systems (IOS). The influences of these multiple levels of governments on IOS are of an enormous scale and impact on businesses and national economies. Understanding them is a prerequisite for informed actions. From a theoretical point of view we contribute with the MLxMC framework, a conceptual framework, which combines a processual, multi-level approach with the motors of change. We use the MLxMC framework to explicitly highlight the influences of multiple levels of governments on IOS developments that take place in the highly regulated environment of international trade. We demonstrate how the framework can be applied to analyze such developments, extending the existing IOS research with models that explicitly acknowledge the role of government. The framework makes use of multi-level analysis by taking the political and institutional aspects into account. As an analytical tool, the framework can support business practitioners as well as policy-makers in their strategic choices of which level to engage at and with whom to collaborate in order to influence the debate. © 2009 Operational Research Society Ltd. All rights reserved.