Background: The Mediterranean region is particularly vulnerable to the effect of summer temperature. Within the CIRCE project this time-series study aims to quantify for the first time the effect of summer temperature in Eastern-Southern Mediterranean cities and compared it with European cities around the Mediterranean basin, evaluating city characteristics that explain between-city heterogeneity. Methods: The city-specific effect of maximum apparent temperature (Tappmax) was assessed by Generalized Estimation Equations, assuming a linear threshold model. Then, city-specific estimates were included in a random effect meta-regression analysis to investigate the effect modification by several city characteristics. Results: Heterogeneity in the temperature-mortality relationship was observed among cities. Thresholds recorded higher values in the warmest cities of Tunis (35.5 degrees C) and Tel-Aviv (32.8 degrees C) while the effect of Tappmax above threshold was greater in the European cities. In Eastern-Southern Mediterranean cities a higher effect was observed among younger age groups (0-14 in Tunis and 15-64 in Tel-Aviv and Istanbul) in contrast with the European cities where the elderly population was more vulnerable. Climate conditions explained most of the observed heterogeneity and among socio-demographic and economic characteristics only health expenditure and unemployment rate were identified as effect modifiers. Conclusions: The high vulnerability observed in the young populations in Eastern-Southern Mediterranean cities represent a major public health problem. Considering the large political and economic changes occurring in this region as well future temperature increase due to climate change, it is important to strengthen research and public health efforts in these Mediterranean countries.