Background: The nature of wheezing after respiratory syncytial virus lower respiratory tract infection (RSV LRTI) is usually transient. However, some children will develop persistent or late wheezing. Objective: We hypothesized that early and late postbronchiolitis wheezing are determined by distinct clinical, immunologic, and genetic variables. Methods: A cohort of 101 children hospitalized for RSV LRTI was prospectively followed for 6 years. During RSV LRTI, cytokine studies were performed and genetic polymorphisms were determined. Parents performed daily log registration of respiratory symptoms during the first 3 years of follow-up and again at age 6 years during the winter season. Results: Distinctive associations for early and late postbronchiolitis wheezing were found. We previously showed that airflow limitation during RSV LRTI as well as convalescent monocyte IL-10 production are associated with early wheezing. These variables were not associated with late wheezing. On the other hand, atopic family history was not associated with early wheezing, but it was associated with late wheezing. Most importantly, the IL-13 Gln allele was associated with late wheezing (odds ratio 3.27, 95% confidence interval 1.32-8.06), but it was not associated with early wheezing. Conclusion: This study revealed distinct clinical, immunologic, and genetic determinants of early and late wheezing after RSV LRTI, indicating distinct pathophysiological mechanisms. We conclude that late wheezing at age 6 years, but not early postbronchiolitis wheezing, is an asthmatic phenomenon and genetically related to a functional IL-13 polymorphism. Clinical implications: After RSV LRTI, wheezing at age 6 years is not related to early postbronchiolitis wheezing and represents a distinct disease entity.