Background: Over expression of mucin often leads to serious airway pathologies. The rhizome of Zingiber cassumunar Roxb. (“Phlai” in Thai) has been used as an anti-asthmatic drug in Thai traditional medicine. However, the effect of this plant on mucin production has not been reported. Objective: The aim of the present study was to investigate whether crude ethanolic extracts of Zingiber cassumunar (CEZE) suppress phorbol12-myristate 13-acetate (PMA)-induced mucin production and gene expression in human airway epithelial cells and if so, to examine whether the suppression of mucin gene expression is mediated via the mitogen-activated protein kinase (MAPK) signal transduction pathways. Methods: Confluent NCI-H292 cells were pretreated with CEZE for 2 hours and then stimulated with 100 or 200 nmol/l PMA for 8 h. The levels of MUC2 and MUC5AC mRNA were determined by RT-PCR and real-time PCR. Levels of total mucin; MUC2 and MUC5AC in culture supernatants were measured using ELLA and ELISA assays, respectively. Extracellular signal-regulated kinase (ERK), JNK, p38 MAPK protein levels were analyzed by Western blotting. Results: CEZE (5-100μg/ml) significantly inhibited total mucin production, including MUC2 and MUC5AC mRNA and proteins induced by PMA in NCI-H292 cells. The extracts obviously inhibited the phosphorylation of ERK, but not JNK and p38 in PMA-stimulated NCI-H292 cells. Our results suggest that Z. cassumunar-mediated suppression of PMA-induced MUC2 and MUC5AC mRNA operates via ERK inhibition. Conclusion: Z. cassumunar suppresses PMA-induced MUC2 and MUC5AC gene expression in human airway epithelial cells via inhibition of ERK MAPK-dependent pathway.