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Introduction: IFN lambda (type III‐IFN‐λ1) is a molecule primarily produced by epithelial cells that provides an important first‐line defence against viral respiratory infections and has been linked to the pathogenesis of viral‐induced wheezing in early life. The goal of this study was to better understand the regulation of innate IFN‐lambda responses in vitro in primary human infant airway epithelial cells (AECs) and in vivo using nasal aspirates during viral respiratory infections. Methods: IFN‐lambda protein levels were quantified: (a) in human infant AECs exposed to (poly(I:C) dsRNA) under different experimental conditions (n = 8 donors); and (b) in nasal aspirates of young children (≤3 years) hospitalized with viral respiratory infection (n = 138) and in uninfected controls (n = 74). In vivo IFN‐lambda airway levels during viral infections were correlated with individual characteristics and respiratory disease parameters. Results: Our in vitro experiments showed that the poly(I:C)‐induced innate production of IFN lambda in human infant AECs is regulated by (a) p38‐MAPK/NF‐kB dependent mechanism; and (b) exposure to pro‐inflammatory signals such as IL1β. Our in vivo studies demonstrated that (a) infants (<18 months) had higher virus‐induced IFN‐lambda airway secretion; (b) subjects with RSV infection showed the highest IFN‐lambda airway levels; and (c) individuals with the highest virus‐induced IFN‐lambda levels (>90th percentile) had higher viral loads and were more likely to have respiratory sick visits within 12 months of discharge (OR = 5.8). Conclusion: IFN‐lambda responses to dsRNA in the human infant airway epithelium are regulated by p38‐MAPK and NF‐kB signalling. High in vivo IFN‐lambda production is influenced by virus type and associated with recurrent respiratory sick visits in young children. [ABSTRACT FROM AUTHOR]