The histamine skin response is widely used as a standardized positive control in the performance of skin prick testing. As a part of the Aalst Allergy Study, we investigated whether histamine skin reactivity, using histamine 10 mg/mL, was influenced by age, gender, ethnic origin, environmental exposure, specific sensitization patterns, or other factors. The parents of 2021 nonselected children aged 3.4-14.8 years completed a baseline questionnaire and gave written informed consent for skin prick testing with seven common aeroallergens on their child. Sensitized children had significantly larger histamine wheal sizes than nonsensitized children (mean 4.3 vs 4.0 mm, p < 0.05). A significant difference was found in histamine wheal size between nonsensitized versus multiply sensitized children (p < 0.001), but not between mono-sensitized versus multiply sensitized children (p = 0.105). The only other factors associated with significantly larger histamine wheal sizes were a history of eczema and a history suggestive for asthma on the Brief Pediatric Asthma Screen Plus. The histamine wheal was absent in 8.9% of children. In conclusion, sensitization and some other clinical indicators of atopy were associated with a larger histamine skin wheal. Other conditions including gender and environmental exposure did not have an influence on histamine skin reactivity, which strengthens the use of histamine as a reference in skin prick testing in this age group.