Systemic inflammation is reported to be associated with neutrophilic airway inflammation in asthma, but mechanisms underlying this finding are not well understood. This study aimed to examine the molecular mechanisms of the airway neutrophilia that are associated with systemic inflammation in asthma. Fifty stable nonsmoking adults with asthma had plasma high sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) assayed. Subjects with an elevation of both hsCRP and IL-6 were grouped as asthmatics with systemic inflammation, and those with both hsCRP and IL-6 within the normal ranges were grouped as asthmatics without systemic inflammation. Clinical characteristics and sputum inflammatory cell counts were compared between the two groups. Gene expression profiles from sputum were analyzed and altered expression of four genes (CCL8, IL8RA, SELL, and PI3) was confirmed using quantitative PCR. Asthmatics with systemic inflammation (n=18, 36%) had a higher BMI, greater history of cigarette smoking, lower FVC% predicted, and increased sputum neutrophils compared to those without systemic inflammation (n=16, 32%). Microarray analysis identified 449 genes that were significantly altered in sputum between the two groups. Altered genes were involved in IL-1, TNF-α/nuclear factor-κB, and Kit receptor pathways, and were related to innate immune response, defense and inflammatory response, in particular neutrophilic inflammation. Systemic inflammation was associated with airway neutrophilia in asthma, and was related to a group of differentially expressed genes in the lung involving multiple cytokine pathways. Our findings suggest that targeting systemic inflammation might provide a novel therapeutic strategy for neutrophilic asthma.