Mounting interest in the global system of cities has led many scholars to portray large, world-class cities as control points in the global economy. From this position, they govern global banking, finance and international corporate relations with the assistance of advanced business services and telecommunications. While large cities have taken on many global functions, recent research has cast them only as outposts in the global economy and pays little attention to their role in regional and national economies. This paper explores the role of five large US cities in regional and national economies. Using primary trade data for five high-order business services, we identify the extent to which these large cities trade with other large cities of the US urban system, smaller-sized cities, and test statistically the effect that firm attributes and physical characteristics of the city system have on shaping the areal extent of large city interaction (trade). The results indicate that: trade is consistently biased towards other large cities; the size of origin cities is associated with the size of destination cities; and, distance more so than destination city size plays the dominant role in shaping large city patterns of trade.