It is well understood that transport mode choice is effected by journey-distance and journeytime (Plaut 2005; Pucher and Dijkstra 2003; Schwanen and Mokhtarian 2005; Wardman, Tight, and Page 2007) We also know that configurational attributes effect the locations of retail and commercial activities (Hillier et al. 1993), and these in-turn influence residential location choices. Finally, specific socio-demographic groups have different preferences regarding their choices of transportation. The research reported in this paper sought to investigate whether configuration, along with other planning variables, have a role on transportation mode choice. Since the regularity or deformity of urban grid may have an effect on Space Syntax analysis (Ratti 2004a, 2004b, 2005), two gridded and two non-gridded US cities were chosen. For this investigation seven land use variables, ten socio-economic and demographic variables, and three transportation variables in addition to six traditional Space Syntax variables were collected and used. Data were assembled from online open source databases of the respective cities and the US census bureau. Space Syntax topological and angular analysis of CAD drawn axial lines and street centerlines extracted from GIS maps were performed. ArcGIS spatial analysis tools were applied to combine land use, socio-economic & demographic, transportation and Space Syntax variables to the scale of census block-groups that was selected as the study unit. Several multiple regression and linear regression analyses indicated that renters and non-family households are configurationally separated from homeowners and family households: the former locating themselves in integrated areas where businesses are located. Homeowners and family households prefer segregated areas and tend to drive to work. The results also indicated a definite role of city layouts. One important variation observed in our comparative analysis between gridded and non-gridded cities was that choice was an important indicator for gridded cities while integration was for non-gridded ones. Although the reason for this is speculative at this point, this distinction will serve as an important beginning for future investigations and understanding the particular syntactic properties of gridded American cities.