Background Atopy is an established risk factor for asthma, and an elevated eosinophil level is a hallmark of atopic and non-atopic asthma. Whether atopy and eosinophils act independently or interact to influence asthma has clinical and public health implications. Objective To investigate the relationship between atopy and eosinophils in asthma. Methods Data on current asthma, atopy (IgE positive to 1 allergen), and blood eosinophil percent (dichotomized at the median) were obtained for persons aged 6years from the National Health and Nutrition Examination Survey 20052006. Interaction on an additive scale was evaluated by estimating the prevalences of asthma for combinations of atopy (yes or no) and eosinophil percent (high or low) and calculating the excess prevalence due to interaction. Results For all ages combined, the adjusted prevalences of asthma were 4.6%, 7.6%, 6.9% and 17.2% for persons with neither factor, atopy alone, a high eosinophil percent alone and both factors respectively. The excess prevalence of asthma due to interaction was 7.2%, indicating synergism. The excess prevalence was greatest in children aged 617years (15.3%), and it decreased with each older age category until it was absent in adults aged 55years (0.2%). In children, 94% of asthma cases attributable to the 2 factors were attributable to the interaction, whereas in the oldest adults, no cases were attributable to the interaction. Conclusions and Clinical Relevance Interaction between atopy and an elevated eosinophil level in asthma cases was very strong in children but absent in the oldest adults, which suggests different mechanistic pathways for these factors by age and supports the notion that asthma is a heterogeneous disease. In addition, the age-dependent interaction between the factors has potential implications for the selection of asthma patients for treatments that would target either IgE or a high eosinophil level.