Aim: Nonthermal atmospheric-pressure plasmas offer significant advantages as an emerging disinfection approach. However the mechanisms of inactivation, and thus the means of optimizing them, are still poorly understood. The objective of this study, therefore, was to explore differential gene expression on a genome-wide scale in Escherichia coli following exposure to a nonthermal atmospheric-pressure argon plasma plume using high-density oligonucleotide microarrays. Methods and Results: Plasma exposure was found to significantly induce the SOS mechanism, consisting of about 20 genes. Other genes involved in regulating response to oxidative stress were also observed to be up-regulated. Conversely, the expression of several genes responsible for housekeeping functions, ion transport, and metabolism was observed to be down-regulated. Conclusions: Elevated yet incomplete induction of various DNA damage repair processes, including translesion synthesis, suggests substantial DNA damage in E. coli. Oxidative stress also appeared to play a role. Thus it is proposed that the efficacy of plasma is due to the synergistic impact of UV photons and oxygen radicals on the bacteria. Significance and Impact of the Study: This study represents the first investigation of differential gene expression on a genome-wide scale in an organism following plasma exposure. The results of this study will help enable the design of safe and effective plasma decontamination devices.