Background: Latin America is one of the most unequal regions in the world, but evidence is lacking on the magnitude of health inequalities in urban areas of the region. Our objective was to examine inequalities in life expectancy in six large Latin American cities and its association with a measure of area-level socioeconomic status. Methods: In this ecological analysis, we used data from the Salud Urbana en America Latina (SALURBAL) study on six large cities in Latin America (Buenos Aires, Argentina; Belo Horizonte, Brazil; Santiago, Chile; San José, Costa Rica; Mexico City, Mexico; and Panama City, Panama), comprising 266 subcity units, for the period 2011–15 (expect for Panama city, which was for 2012–16). We calculated average life expectancy at birth by sex and subcity unit with life tables using age-specific mortality rates estimated from a Bayesian model, and calculated the difference between the ninth and first decile of life expectancy at birth (P90–P10 gap) across subcity units in cities. We also analysed the association between life expectancy at birth and socioeconomic status at the subcity-unit level, using education as a proxy for socioeconomic status, and whether any geographical patterns existed in cities between subcity units. Findings: We found large spatial differences in average life expectancy at birth in Latin American cities, with the largest P90–P10 gaps observed in Panama City (15·0 years for men and 14·7 years for women), Santiago (8·9 years for men and 17·7 years for women), and Mexico City (10·9 years for men and 9·4 years for women), and the narrowest in Buenos Aires (4·4 years for men and 5·8 years for women), Belo Horizonte (4·0 years for men and 6·5 years for women), and San José (3·9 years for men and 3·0 years for women). Higher area-level socioeconomic status was associated with higher life expectancy, especially in Santiago (change in life expectancy per P90–P10 change unit-level of educational attainment 8·0 years [95% CI 5·8–10·3] for men and 11·8 years [7·1–16·4] for women) and Panama City (7·3 years [2·6–12·1] for men and 9·0 years [2·4–15·5] for women). We saw an increase in life expectancy at birth from east to west in Panama City and from north to south in core Mexico City, and a core-periphery divide in Buenos Aires and Santiago. Whereas for San José the central part of the city had the lowest life expectancy and in Belo Horizonte the central part of the city had the highest life expectancy. Interpretation: Large spatial differences in life expectancy in Latin American cities and their association with social factors highlight the importance of area-based approaches and policies that address social inequalities in improving health in cities of the region. Funding: Wellcome Trust.