OBJECTIVE: To investigate the role of the Mediterranean diet and physical activity with relation to living environment and childhood asthma. METHODS: 1125 children (529 boys), 10 to 12 years old were recruited either in an urban environment (Athens, n = 700) or rural environment (n = 425) in Greece. A path analytic model was developed to assess the causal relation between urban environment and asthma prevalence (standardized ISAAC questionnaire), through the mediation of the Mediterranean diet (evaluated by the KIDMED food frequency questionnaire) and physical activity (evaluated by the PALQ physical activity questionnaire). RESULTS: The proposed model had a very good fit (χ2/df ratio =1.05, RMSEA=0.007, 90% confidence interval: 0.01 to 0.046, p=0.97, CFI = 0.98). A significant total positive effect was found between urban environment and asthma symptoms (standardized beta= 0.09, p<0.001). Adherence to the Mediterranean diet was related negatively with asthma symptoms (standardized beta = -0.224, p<0.001). An inverse mediating effect of the Mediterranean diet was observed for the urban environment - asthma relation (standardized beta=-0.029, p<0.001) while physical activity had no significant contribution (p=0.62), adjusted for several confounders. CONCLUSIONS: The Mediterranean diet may protect against the harmful effect of urban environment on childhood asthma.