Background: As early and appropriate care of severe septic patients is associated with better outcome, understanding of very first events in the disease process is needed. Pan-genomic analyses offer an interesting opportunity to study global genomic response within the very first hours after sepsis. The objective of this study was to investigate the systemic genomic response in severe Intensive Care Unit (ICU) patients and determine whether patterns of gene expression could be associated with clinical severity evaluated by severity score. Methods: Twenty-eight ICU patients were enrolled at the onset of septic shock. Blood samples were collected within 30 minutes, 24 and 48 hours after shock and genomic response was evaluated using microarrays. The genome wide expression pattern of blood leukocytes was sequentially compared to healthy volunteers and after stratification based on SAPSII score to identify potential mechanisms of dysregulation. Results: Septic shock induces a global reprogramming of the whole leukocyte transcriptome affecting multiple functions and pathways (> 71% of the whole genome was modified). Most altered pathways were not significantly different between SAPSII-high and SAPSII-low groups of patients. However the magnitude and the duration of these alterations were different between these two groups. Importantly, we observed that the more severe patients did not exhibit the strongest modulation. This indicates that some regulation mechanisms leading to recovery seem to take place at early stage. Conclusion: In conclusion, both pro- and anti-inflammatory processes, measured at the transcriptomic level, are induced within the very first hours after septic shock. Interestingly, the more severe patients did not exhibit the strongest modulation. This highlights that, not only the responses mechanisms by themself but mainly their early and appropriate regulation, are crucial for patient recovery. This reinforces the idea that an immediate and tailored aggressive care of patients, aimed at restoring an appropriately regulated immune response, may have a beneficial impact on outcome.