Several studies have shown a higher prevalence of positive skin-prick tests to airborne allergens in Western than in Eastern European countries. We have recently reported that skin histamine reactivity significantly increased in Italy over the past 15 years. Population differences in skin histamine reactivity could, at least in part, explain the reported differences in positive allergen skin tests. To test this hypothesis we compared histamine skin reactivity and the prevalence of allergen positive skin-prick tests in a sample of Italian and Polish schoolchildren. A total of 336 unselected 9-year-old-schoolchildren (198 in Italy and 138 in Poland) underwent skin-prick tests with three different histamine concentrations (10, 1 and 0.2 mg/ml) and with a panel of common airborne allergens according to the ISAAC protocol, phase two. Mean wheals elicited by skin-prick tests with the three serial concentrations of histamine were significantly larger (p < 0.001) and shifted more toward higher values (p < 0.001) in Italian than in Polish children. The differences were greater for the intermediate histamine concentration tested (1 mg/ml) than for the highest concentration (10 mg/ml). Skin-prick tests for airborne allergens were more frequently positive in Italian children: wheals ≥ 3 mm induced by any allergen [odds ratio (OR) 1.69; confidence interval (CI) 0.98–2.92] by Dermatophagoides pteronyssinus (OR 1.92; CI 0.97–3.80) and by D. farinae (OR 3.15; CI 1.16–8.63). Labeling as positive allergen wheal reactions half the size of the 10 mg/ml histamine wheal or larger reduced but did not abolish the Italian–Polish differences. The significantly higher skin histamine reactivity observed in Italian children could help to explain why allergen skin-test reactions differ in the East and West European populations. Moreover, differences in nonallergen-specific factors among populations should be considered in the interpretation of skin test results (e.g. cut-off points). To obtain meaningful results, epidemiological studies of allergies should include serial histamine dilutions.