The present experiments were designed to characterize by microarray analysis the transcriptional responses of human keratinocytes (HaCat) to TNF-α and IL-1 β, given alone or in combination, in order to better understand the mechanisms underlying inflammatory, immune responses and cell death in which both cytokines play a pathophysiological role. Significant differences in the percentage and quality of genes dysregulated by TNF-α and IL-1 β were shown. Both cytokines activated a series of genes involved in inflammatory, immune response as well as in cell death. In our experimental conditions, TNF-α, in contrast to IL-1 β, did not induce a significant level of apoptosis in keratinocytes. However, given together both cytokines produced a significant decrease in apoptotic cells and synergistic transcriptional response which was due to the activation of several specific genes occurring after application of each cytokine. TNF-α and IL-1 β evoked apoptotic effect and transcriptional responses were linked to the stimulation of their specific receptors since a pre-treatment with monoclonal antibodies vs TNF-α and/or IL-1 β receptors was able to significantly reduce them.