Background Infants hospitalized for bronchiolitis (severe bronchiolitis) are at high risk for developing childhood asthma. However, the pathobiological link between these conditions remains unclear. We examined the longitudinal relationship of periostin (an extracellular matrix protein upregulated in response to type 2 inflammation) during bronchiolitis with the subsequent development of asthma. Methods In a 17‐center prospective cohort study of infants (aged <1 year) with severe bronchiolitis, we measured the serum periostin level at hospitalization and grouped infants into 3 groups: low, intermediate, and high levels. We examined their association with asthma development by age 6 years and investigated effect modification by allergic predisposition (eg, infant's IgE sensitization). Results The analytic cohort consists of 847 infants with severe bronchiolitis (median age, 3 months). Overall, 28% developed asthma by age 6 years. In the multivariable model adjusting for nine patient‐level factors, compared to the low periostin group, the asthma risk was significantly higher among infants in the intermediate group (23% vs. 32%, OR 1.68, 95%CI 1.12–2.51, p = .01) and non‐significantly higher in the high‐level group (28%, OR 1.29, 95%CI 0.86–1.95, p = .22). In the stratified analysis, infants with IgE sensitization had a significantly higher risk for developing asthma (intermediate group, OR 4.76, 95%CI 1.70–13.3, p = .002; high group, OR 3.19, 95%CI 1.08–9.36, p = .04). By contrast, infants without IgE sensitization did not have a significantly higher risk (p > .15). Conclusions In infants with severe bronchiolitis, serum periostin level at bronchiolitis hospitalization was associated with asthma risk by age 6 years, particularly among infants with an allergic predisposition. In this study, a higher serum periostin level at bronchiolitis hospitalization was associated with a greater risk for subsequently developing asthma. The longitudinal relationship was observed mainly in infants with an allergic predisposition. Our findings not only provide an evidence base for early identification of children at high risk for asthma but also offer potential opportunities for early preventive interventions.Abbreviations: CI, confidence interval; IgE, immunoglobulin E