Urbanization is linked to economic growth, and agglomeration economies mean that people in larger cities are more productive. However, urban expansion is also associated with congestion, localized environmental damage, and potentially, social segregation. In this paper we examine how urban expansion and changing urban spatial structure affects the level and scale of socioeconomic segregation of cities in Mexico. We measure different dimensions of urban spatial structure, and segregation by income and education at different geographic scales in 100 Mexican cities from 1990 to 2010. We then examine correlations between the two sets of variables, and run multivariate regressions to assess how changes in urban spatial structure relate to changes in the level and scale of segregation. Findings reveal that as cities expand, inhabitants experience greater levels of socioeconomic segregation, especially at a larger geographic scale. However, an increasing centralization of cities is associated with less segregation. This process works differently for segregation by education and income. For the former, less educated households are become more segregated in expanding, centralizing cities. For the latter, it is high-income households who are becoming more isolated. This study reveals provocative generalizations about the association between urban expansion and increasing segregation in Mexico. It suggests that movements into and out of central cities, rather than urban fragmentation or sprawl, shape how household mobility reorganizes social space.