Mucus hyperproduction is a hallmark of chronic airway inflammatory diseases, such as asthma and COPD. Mucus production in a population of patients with severe asthma does not respond to steroids. However, the underlying mechanism of this steroid-resistance remains incompletely understood. In our pharmacological study with house dust mite (HDM)-sensitized asthmatic mice, we have found that MUC5AC mucus gene expression was steroid resistant, although the number of eosinophil was significantly decreased. In these mice treated with DEX, the expression level of IL-17A and IL-13 was considerably high, as well as MUC5AC. We also found that intratracheal administration of both IL-17A and IL-13 was sufficient to induce steroid-resistant MUC5AC production in lung, whereas IL-17A or IL-13 alone was not. Furthermore, HDM-induced steroid-resistant MUC5AC production was partially reversible with DEX in mice lacking IL-17A. Collectively, these results suggest that the coordinated action of IL-17A and IL-13 mediates steroid-resistant mucus production in mouse model of asthma.