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. In a 17-center prospective cohort study of infants (aged <1year) with severe bronchiolitis, we measured the serum periostin level at hospitalization and grouped infants into 3groups: low, intermediate, and high levels. We examined their association with asthma development by age 6years and investigated effect modification by allergic predisposition (eg, infant's IgE sensitization). The analytic cohort consists of 847 infants with severe bronchiolitis (median age, 3months). Overall, 28% developed asthma by age 6years. 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). In infants with severe bronchiolitis, serum periostin level at bronchiolitis hospitalization was associated with asthma risk by age 6years, particularly among infants with an allergic predisposition.