The fourth millennium BCE was an important period in the expansion of regional interactions across Southwest Asia. During this period, relations between southern Mesopotamia and western and southwestern Iran expanded, as reflected in archaeological evidence from Susa and Susiana, Chogha Mish, Deh Luran, and Godin Tepe. Using a historical-comparative approach and drawing on the Uruk World System theory, this study examines the nature of these relations and their association with economic dependence and political control. Comparative evidence shows that these interactions did not follow a uniform pattern. In later phases, Susa displays greater potential for intermediation; at Chogha Mish, some Uruk-related ceramic forms were produced locally and related administrative practices were adopted; at Tepe Farukhabad, regional interaction coexisted with the persistence of local subsistence strategies; and at Godin Tepe, recent research has weakened the interpretation of the site as a wholly foreign outpost. Accordingly, relations between western and southwestern Iran and southern Mesopotamia are best understood as a diverse network of exchange, technology transfer, intermediation, and possible limited movement of people that did not necessarily entail economic dependence or direct political domination.