Inflammation and edema are associated with respiratory and cutaneous exposure to sulfur mustard (SM) as well as with phosgene-induced lung injury. IL-8 is a key chemotactic inflammatory cytokine that recruits neutrophils and contributes to progression of acute lung injury caused by inhalation of these chemical agents. In the present study, human lung small airway cell (HSAC) cultures were exposed to either SM 25 to 400 μM or phosgene 0.1 to 6.4 ppm • min. IL-8 was increased after exposure to either SM or phosgene. In HSAC cultures exposed to SM (100 μM) and phosgene (1.6 ppm • min), IL-8 was increased above controls by 1013 +123 pg/ml and 965 +181 pg/ml, respectively. Exposure to higher concentrations of either agent increased cytotoxicity and reduced IL-8 towards levels observed in unexposed control HSAC. Ibuprofen has shown efficacy against phosgene pulmonary toxicity in mice. Ibuprofen (62, 125, 250, 500, 1000 μM) significantly diminished phosgene-increased IL-8 in HSAC cultures exposed to 2 ppm • min phosgene. Maximum inhibition of nearly 50% of phosgene-increased IL-8 was seen at 125 and 250 μM doses of ibuprofen (from 1141 +143 pg/ml to 628 +105, 593 +69 pg/ml respectively). Chemical insult-induced increased IL-8 in HSAC cultures provides an assay for screening countermeasures against the inhalation toxicity of chemical threat agents. The increase in the inflammatory cytokine IL-8 by both SM and phosgene may further provide common pharmacological targets for drugs with multithreat medical countermeasure (MTMC) action against distinct chemical threats.