Rationale: Monocytes are central to the initiation of the inflammatory response in sepsis, with caspase-1 activation playing a key role. Monocyte deactivation during sepsis has been linked to poor outcomes. Objectives: Given the importance of caspase-1 in the immune response, we sought to investigate whether monocytes from patients early in septic shock demonstrate alterations in mRNAs for caspase-1 related molecules. Methods: Septic shock patients (n = 26) age > 18, critically ill ICU patients (n=20) and healthy volunteers (n =22) were enrolled in a prospective cohort study in a university intensive care unit. Demographic, biological, physiologic, and plasma cytokine measurements were obtained. Monocytes were assayed for ex vivo TNF production and fresh monocyte mRNA was analyzed by quantitative reverse transcription polymerase chain reaction for Toll-like receptors (TLR), NOD-LRR proteins (NLR), cytokines, and NF-B related genes. Main results: Relative copy numbers for the inflammasome mRNAs for ASC, caspase-1, NALP1 and Pypaf-7 were significantly lower in septic shock patients compared to critically ill controls. Of note, NALP1 mRNA levels were linked to survival in sepsis patients (p = 0.0068) and also correlated with SAPS II scores (r = -0.63). Conclusions: These data suggest that monocyte deactivation occurs during the earliest stages of the systemic inflammatory response and that changes in inflammasome mRNA expression are part of this process.