OBJECTIVE: This study evaluated the interrelationships of living environment, physical activity, lifestyle/dietary habits, and nutritional status on the prevalence of childhood asthma. METHODS: In a cross-sectional survey 1125 children (529 boys), 10 to 12 years old, were selected from 18 schools located in an urban environment (Athens, n = 700) and from 10 schools located in rural areas (n = 425) in Greece. RESULTS: Children living in Athens had higher likelihood of "ever had" asthma compared with children living in rural areas (odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.25-2.54), after adjusting for age and sex. After adjusting for age, sex, body mass index, and adherence to the Mediterranean diet (KIDMED score), leisure-time physical activity was inversely associated with "ever had" asthma. When stratifying by county of residence, a trend toward reduced asthma symptoms among children engaged in outdoor physical activities during their leisure time who reside in rural (but not urban) environment was observed (OR = 0.88, 95% CI = 0.77-1.01). CONCLUSIONS: The inverse relationship between asthma symptoms and leisure-time physical activity in the rural environment and the lack of an association between asthma symptoms and organized sports-related activities should draw the attention of public healthcare authorities. Their efforts should focus on the planning of a sustainable natural environment, which will promote the physical health of children and reduce the burden of childhood asthma.