The NLRP3 inflammasome is a multiprotein complex regulating the secretion of IL-1β and IL-18 in response to a variety of stimuli, including pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). Upon activation, the apoptosis associated speck-like protein (ASC) adaptor recruits caspase-1 to the NLRP3 inflammasome complex, where it first undergoes auto-cleavage and then processes the inactive precursors of IL-1β and IL-18. Importantly, NLRP3 is not responsive to stimulation unless primed by an NF-κB-triggering signal, such as LPS. Recent studies have identified an alternative mechanism leading to caspase-1 activation in mouse. This “non-canonical” pathway requires the inflammatory caspase-11 participating to the regulation of IL-1α, in addition to IL-1β and IL-18. It was also reported that Gram-negative bacteria, but not Gram-positive bacteria, or intracellular LPS are the main triggers of the non-canonical pathway. In vivo evidences indicate that, the non-canonical pathway seems detrimental in murine models of sepsis. However, the existence and the relevance of the non-canonical inflammasome in humans have not been demonstrated yet. Thus, we investigated whether the inflammatory caspase-4 and caspase-5 - human homologs of murine caspase-11- are induced in human monocytes after TLR4 stimulation by LPS. We found that caspase-5, but not caspase-4, is activated in LPS-treated monocytes. Importantly, the release of IL-1β and IL-1α depends on caspase-5 through a mechanism that requires SYK, PLCg and calcium (Ca2+) flux.