We wanted to test the hypothesis that the efficacy of systemic corticosteroid is associated with atopic characteristics in wheezing children. A randomized controlled trial comparing oral prednisolone (2 mg/kg/day in 3 divided doses for 3 days) with placebo in hospitalized wheezing children (n = 266, median 1.6 years, range 3 months to 15.2 years) was conducted. In this post-hoc analysis, we assessed the link between the efficacy of prednisolone and several atopic characteristics, such as atopy, aeroallergen sensitization, total IgE level, number of sensitizations, eczema, atopic eczema, blood or nasal eosinophils, exhaled nitric oxide, positive modified asthma predictive index/asthma, inhaled corticosteroid medication and parental asthma/allergy. Virology was studied comprehensively. Our primary endpoint was the time until ready for discharge, and the most important secondary endpoint was the occurrence of relapses during the following 2 months. For statistics, we used interaction analyses in uni- and multivariate regression models. Overall, prednisolone did not decrease any of our predefined clinical endpoints. Neither was the efficacy of prednisolone associated with atopy. However, prednisolone significantly decreased the time until ready for discharge in children with positive modified asthma predictive index/asthma, inhaled corticosteroids, or rhinovirus infection and/or in children without azithromycin treatment. Prednisolone significantly decreased relapses in children with eczema, nasal eosinophilia and rhinovirus infection. The multiple clinical, inflammatory and viral markers associating with the efficacy of prednisolone should be confirmed in prospective trials. It is important that corticosteroid intervention trials have strict design for these potentially confounding factors.