CD38 is involved in airway function, IL-13-induced airway hyperresponsiveness (AHR), and is regulated by tumor necrosis factor (TNF)- in airway smooth muscle (ASM) cells. This study aimed to determine whether TNF--induced CD38 up-regulation in ASM cells contributes to AHR, a hallmark of asthma. We hypothesized that AHR would be attenuated in TNF--exposed CD38-deficient (CD38KO) mice compared to wild-type (WT) controls. Mice (n=6-8/group) were intranasally challenged with vehicle control or TNF- (50 ng) once, and every-other-day during one or four weeks. Lung inflammation and AHR, measured by changes in lung resistance after inhaled methacholine, were assessed 24 hours following the last challenge. Tracheal rings were incubated with TNF-(50 ng/ml) to assess contractile changes in the ASM. While a single TNF- challenge caused no airway inflammation, both multiple-challenge protocols induced equally significant inflammation in CD38KO and WT mice. A single intranasal TNF-challenge induced AHR in the WT but not in the CD38KO mice, whereas both mice developed AHR after one week of challenges. The AHR was suppressed by extending the challenges for four weeks in both mice, although to a larger magnitude in the WT than in the CD38KO mice. TNF- increased ASM contractile properties in tracheal rings from WT but not from CD38 KO mice. In conclusion, CD38 contributes to TNF--induced AHR after a brief airway exposure to the cytokine, likely by mediating changes in ASM contractile responses, and is associated with greater AHR remission following chronic airway exposure to TNF-. The mechanisms involved in this remission remain to be determined.