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Background Several studies highlighted a great variability, both between and within countries, in the prevalence of asthma and chronic airways diseases. Aim To evaluate if geo-climatic variations can explain the heterogeneity in the prevalence of asthma and respiratory diseases in Italy. Methods Between 2006 and 2010, a postal screening questionnaire on respiratory health was administered to 18,357 randomly selected subjects, aged 20–44, living in 7 centers in northern, central, and southern Italy. A random-effects meta-analysis was fitted to evaluate the between-centers heterogeneity in the prevalence of asthma, asthma-like symptoms, allergic rhinitis, and chronic bronchitis (CB). A principal component analysis (PCA) was performed to synthetize the geo-climatic information (annual mean temperature, range of temperature, annual rainfalls, global solar radiations, altitude, distance from the sea) of all the 110 Italian province capital towns. The associations between these geo-climatic components obtained with PCA and the prevalence of respiratory diseases were analyzed through meta-regression models. Results 10,464 (57%) subjects responded to the questionnaire. There was a significant between-centers heterogeneity in the prevalence of asthma (I 2 = 59.5%, p = 0.022) and CB (I 2 = 60.5%, p = 0.019), but not in that of asthma-like symptoms or allergic rhinitis. Two independent geo-climatic components explaining together about 80% of the overall geo-climatic variability were identified: the first principally summarized the climatic variables; the second the topographic ones. Variations in the prevalence of asthma across centers were significantly associated with differences in the climatic component (p = 0.017), but not with differences in the topographic one. Conclusions Our findings suggest that climate play a role in determining the between-center heterogeneity in the prevalence of asthma in Italy, with higher prevalence in dry-hot Mediterranean climates, and lower in rainy-cold northern climates. [ABSTRACT FROM AUTHOR]