Silver nanoparticles (Ag-NPs) have well-known antimicrobial properties and have been widely applied as nano-strategies in myriad medical fields. Indeed, early growth response (Egr-1) is an important transcription factor that has been implicated in numerous inflammatory diseases. The administration of Ag-NPs transiently increased the levels of Egr-1 mRNA in human keratinocytes with maximal induction at the 30 minute time point. In an effort to identify molecular signatures associated with cellular responses to Ag-NPs, we adopted an approach involving gene expression profiling of human keratinocytes treated with or without Egr-1 siRNA transfection using a cDNA microarray. The microarray analysis demonstrated that: the expression profile of the genes involved in inflammation and immune response were either stimulated or repressed. Overall, this study was sufficient to reliably recognize the engagement of Egr-1-driven molecular signaling pathways in Ag-NPs-treated keratinocytes.