The mechanisms involved in chronic pain and inflammation have come under intense scrutiny in the last two decades. With non-steroidal anti-inflammatory drugs (NSAIDs) providing suboptimal relief for inflammatory pain, the targeting of other pro-inflammatory pathways is being investigated for therapeutic application. The purinergic receptor P2X7 is thought to regulate the activation of caspase-1, which subsequently cleaves pro-interleukin-1β (IL-1β), thereby causing the secretion of mature IL-1β. In this study, we utilized an ex vivo stimulation of human peripheral blood with variable duration lipo-polysaccharide (LPS) priming and examined the effects of ATP, P2X7 antagonists, and NSAIDS on IL-1β and caspase-1. We observed that following LPS priming, the P2X7 agonist and ATP analogue BzATP markedly stimulated IL-1β secretion. Interestingly, BzATP also stimulated the secretion of caspase-1 itself in a dose and time-dependent manner that paralleled the secretion of IL-1β, which was also dependent upon LPS priming. The secretion of both IL-1β and caspase-1 was almost completely blocked by the P2X7 antagonists PPADS and AZ11645373. Moreover, secretion of both IL-1β and caspase-1 was inhibited by AZ11645373 in a parallel, dose-dependent manner. In contrast, NSAIDS were unable to inhibit secretion of either IL-1β or caspase-1. These results suggest that both ATP-induced IL-1β secretion and caspase-1 secretion are mediated almost entirely through the P2X7 receptor. These data also further indicate that by inhibiting IL-1β and caspase-1 secretion, P2X7 antagonism may represent a novel mechanism to inhibit pain and inflammation that is not achievable with currently available NSAIDS.