Introduction <p>Interferon-lambda 3 (IFN-λ3) plays a crucial role in antiviral defense but may also influence asthma development. We hypothesized that infants carrying the <i>rs12979860</i>(TT) and <i>rs8099917</i>(GG) genotypes, associated with lower IFN-λ3 expression, who experience early-life bronchiolitis, are more susceptible to developing persistent asthma.</p> Methods <p>A 4-year prospective follow-up study of a post-bronchiolitis cohort of 666 children was conducted. The primary outcome was a diagnosis of persistent asthma 4 years after discharge. IFN-λ3 SNPs information and clinical data were collected from earlier reports, medical records, and questionnaires.</p> Results <p>26.3% (<i>n</i> = 175) of the children developed physician-diagnosed asthma. Multivariate analysis identified parental history of asthma and the IFN-λ3 <i>rs12979860</i>(TT) genotype as independent risk factors in boys (Hazard ratio: 1.7 (95% CI: 1.04-2.98)) who experienced a Respiratory Syncytial virus (RSV)-bronchiolitis before 6 months of age. Uncontrolled asthma status at 4 years after discharge was associated with <i>rs12979860</i>(TT) and <i>rs8099917</i>(GG) genotypes in boys and girls.</p> Conclusion <p>The <i>rs12979860</i>(TT) genotype is a sex-specific genetic risk factor for persistent asthma in boys who experience RSV-bronchiolitis before the age of 6 months, revealing a complex gene-environment-sex interaction that determines long-term respiratory outcomes.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>Asthma is a chronic, heterogeneous pulmonary disease characterized by the inflammation of the lower respiratory tract. In this study, we identify a novel genetic marker associated with IFN-λ3 expression levels, which, when combined with children’s clinical history of bronchiolitis, could aid in the early identification of those at higher risk of developing asthma and of uncontrolled asthma before the age of 5.</p> </ItemContent> </UnorderedList></p>