Cyclooxygenase 2 (COX2), a key regulatory enzyme of the prostaglandin/eicosanoid pathway, is an important target for anti-inflammatory therapy. It is highly induced by pro-inflammatory cytokines in a Nuclear factor kappa B (NFkappaB)-dependent manner. However, the mechanisms determining the amplitude and dynamics of this important pro-inflammatory event are poorly understood. Furthermore, there is significant difference between human and mouse COX2 expression in response to the inflammatory stimulus tumor necrosis factor alpha (TNFalpha). Here, we report the presence of a molecular logic AND gate composed of two NFkappaB response elements (NREs) which controls the expression of human COX2 in a switch-like manner. Combining quantitative kinetic modeling and thermostatistical analysis followed by experimental validation in iterative cycles, we show that the human COX2 expression machinery regulated by NFkappaB displays features of a logic AND gate. We propose that this provides a digital, noise-filtering mechanism for a tighter control of expression in response to TNFalpha, such that a threshold level of NFkappaB activation is required before the promoter becomes active and initiates transcription. This NFkappaB-regulated AND gate is absent in the mouse COX2 promoter, most likely contributing to its differential graded response in promoter activity and protein expression to TNFalpha. Our data suggest that the NFkappaB-regulated AND gate acts as a novel mechanism for controlling the expression of human COX2 to TNFalpha, and its absence in the mouse COX2 provides the foundation for further studies on understanding species-specific differential gene regulation.