We describe the molecular features of the interferon (IFN)‐γ‐mediated transcription of the human intercellular adhesion molecule (ICAM‐1) gene. We identified putative IFN‐γ‐activated sites (GAS) distributed throughout a large segment of the ICAM‐1 promoter (4.0 kb region). Using computer‐assisted search, these sequences were similar to potential IFN‐γ responsive elements that have a core sequence 5′‐TTNCNNNAA‐3′. In this report we show that in the ICAM‐1 promoter a GAS site is located at −115 from the translation initiation site, and binds with strong affinity to IFN‐γ‐activated Signal Transducers and Activators of Transcription (STAT1) homodimers. The same sequence is responsible for the IFN‐γ‐mediated transcription of the ICAM‐1 gene. Moreover, we present evidence that a more distal GAS element that maps at −2787 from the translation initiation site, binds IFN‐γ‐activated STAT1 dimers with lower affinity. Multimeric copies of such GAS sequence inserted into a tkCAT minimal promoter can drive transcription, demonstrating that the −2787 bp GAS element has an independent functional activity upon binding of IFN‐γ‐activated STAT1 proteins as documented by in vitro binding assays. Furthermore, using recombinant ICAM‐CAT mutants, we show that, in vivo, the −2787 GAS, but not a mutagenized −2787 GAS site, when coupled to the more proximal −115 GAS element, has an additive effect in enhancing the IFN‐γ‐mediated transcription of ICAM‐1 promoter. Nevertheless, using a recombinant construct bearing the wild type −2787 GAS element and a mutagenized −115 GAS element, we could not detect any transcription after transfection of U937 recipient cells, suggesting that the −2787 bp GAS element is not sufficient as such for gene activation, but can cooperate with its cognate proximal sequence to give full function to the ICAM‐1 promoter during the IFN‐γ response. Taken together these data provide evidence that two GAS sites are required for the full potential activity in the mechanism of ICAM‐1 gene activation by IFN‐γ.