Purpose: Cold air exposure is associated with increased respiratory morbidity and mortality. Repeated inhalation of cold and dry air is considered the cause of the high prevalence of asthma among winter endurance athletes. This study assessed whether a heat- and moisture-exchanging breathing device (HME) attenuates airway responses to high-intensity exercise in sub-zero temperatures among healthy subjects. Methods: Using a randomized cross-over design, 23 healthy trained participants performed a 30-min warm-up followed by a 4-min maximal, self-paced running time trial in − 15 °C, with and without HME. Lung function was assessed pre- and immediately post-trials. Club cell protein (CC-16), 8-isoprostane, and cytokine concentrations were measured in plasma and urine pre- and 60 min post trials. Symptoms were assessed prior to, during, and immediately after each trial in the chamber. Results: HME use attenuated the decrease in forced expiratory volume in 1 s (FEV1) post trials (∆FEV1: mean (SD) HME − 0.5 (1.9) % vs. no-HME − 2.7 (2.7) %, p = 0.002). HME also substantially attenuated the median relative increase in plasma-CC16 concentrations (with HME + 27% (interquartile range 9–38) vs no-HME + 121% (55–162), p < 0.001) and reduced airway and general symptom intensity, compared to the trial without HME. No significant changes between trials were detected in urine CC16, 8-isoprostane, or cytokine concentrations. Conclusion: The HME attenuated acute airway responses induced by moderate-to-maximal-intensity exercise in − 15 °C in healthy subjects. Further studies are needed to examine whether this HMEs could constitute primary prevention against asthma in winter endurance athletes.