We tested whether cystic fibrosis (CF) airway epithelia have larger innate immune responses than non-CF or CFTR-corrected cells, perhaps resulting from ER stress due to retention of F508CFTR in the endoplasmic reticulum (ER) and activation of Ca²⁺ (Ca_i) and NF-B signaling. Adenovirus (adv) infections of a human cystic fibrosis (F508/F508) nasal cell line (CF15) provided isogenic comparisons of wtCFTR and F508CFTR. In the absence of bacteria, there were no or only small differences among CF15, CF15-lacZ (-galactosidase-expressing), CF15-wtCFTR (wtCFTR-corrected) and CF15-F508CFTR (to test ER retention of F508CFTR) cells in: NF-B activity, IL8 secretion, Ca_i responses and ER stress. Non-CF and CF primary cultures of human bronchiolar epithelial cells (HBE) secreted IL8 equivalently. Upon infection with Pseudomonas aeruginosa (PA) or flagellin (key activator for airway epithelia), CF15, CF15-lacZ, CF15-wtCFTR and CF15F508CFTR cells exhibited equal PA binding, NF-B activity and IL8 secretion; cells also responded similarly to flagellin when both CFTR (forskolin) and Ca_i signaling (ATP) were activated. CF and non-CF HBE responded similarly to flagellin+ATP. Thapsigargin (Tg, releases ER Ca²⁺) increased flagellin-stimulated NF-B and ER stress similarly in all cells. We conclude that ER stress, Ca_i and NF-B signaling and IL8 secretion were unaffected by wt- or F508CFTR in control and during exposure to PA, flagellin, flagellin+ATP or flagellin+ATP+forskolin. Tg, but not wt- or F508CFTR, triggered ER stress. Previously measured hyperinflammatory responses in CF airway epithelia may have resulted from cell-specific, rather than CFTR- or F508CFTR-specific effects.