This paper investigates the nature of port-city relationships in two major port regions of the world, Europe and Asia. Although this issue is well analyzed through either isolated case studies or general models, it proposes a complementary approach based on urban and port indicators available for 121 port cities. In terms of demographic size and container traffic, it shows the decline of port-urban dependence, stemming from changes in global transportation and urban development. However, European and Asian port cities are not identically confronted to the same challenges, notably in terms of their hinterlands. A factor analysis highlights a regional differentiation of port-city relationships according to their insertion in both urban and port systems, with a core-periphery dualism in Europe and a port-city hierarchy in Asia. Thus, the distance to inland markets for European ports and the size of coastal markets for Asian ports are the main factors to explain the nature of port-city relationships in the two areas. It helps to evaluate which European and Asian port cities are comparable beyond their cargo volumes, by putting together micro (local environments) and macro (regional patterns) factors.