Cigarette smoke is a complex chemical mixture that includes compounds associated with oxidative stress, inflammation and DNA damage. Our laboratory previously reported that smoke condensate from cigarettes that primarily heat tobacco produce less change in p21, GADD45, COX-2 and IL-8 mRNA levels in NHBE cells than smoke condensate from tobacco-burning cigarettes. The objective of this study was to characterize the effect of smoke condensates from tobacco-heating and tobacco-burning cigarettes on genes involved in NF-κB signal transduction, a pathway reported to mediate in part the response of bronchial epithelial cells to cigarette smoke. In addition to COX-2, genes coding for HO-1, G-CSF, HSP-70 and TNF-α have been identified as being involved in NF-κB signal transduction. Cigarette smoke condensate (CSC) was prepared from Kentucky 1R4F cigarettes, a tobacco-burning product designed to represent the average low "tar" cigarette in the US market and Eclipse, a cigarette that primarily heats tobacco. Following CSC exposures, changes in mRNA and protein were determined by quantitative RT/PCR and cytokine analyses, respectively. HO-1 and HSP-70 mRNA levels were significantly increased (p<0.05) in cells exposed to K1R4F compared to Eclipse. K1R4F smoke condensate caused a dose-dependent, statistically-significant decrease in TNFα mRNA levels while Eclipse samples were only moderately changed from control values. Cytokine secretion analysis did not reveal differences in TNF-α levels secreted in the media from either condensate exposure, while G-CSF secretion was altered to a lesser degree in NHBE cells treated with Eclipse condensate compared to K1R4F condensate. The present data suggest that the characterization of genes involved in key signal transduction pathways (i.e. NF-κB) following cigarette smoke exposure in an in vitro human bronchial epithelial cell model may serve as biomarkers of effect for assessing potential reduced-risk cigarettes.