We have previously shown that expression of a Ca2+-activated Cl- channel (mCLCA3 in mice and bCLCA1 in humans) is up-regulated along with goblet cell metaplasia and mucus overproduction in the lungs of interleukin 9 (IL9) transgenic mice, and in human primary lung cultures by IL4, IL13 and IL9. We show here that hCLCA1 expression in NCI-H292 cells specifically induces soluble gel-forming mucin production. Moreover, niflumic acid (NFA), a blocker of hCLCA1-dependent Cl- efflux, inhibits MUC5A/C production in these cells. NFA treatment during natural antigen-exposure, where mCLCA3 is greatly up-regulated in the lung, significantly reduces airway inflammation, goblet cell metaplasia and mucus overproduction in vivo. These data suggest that this Ca2+-activated Cl- channel plays an important role in epithelial-regulated inflammatory responses, including goblet cell metaplasia, and represents a potential novel therapeutic target for the control of mucus overproduction in chronic pulmonary disorders.