Monocytes play an important role in inflammation, angiogenesis, and atherosclerosis. During these processes monocytes release pre-formed proinflammatory mediators from granules, and synthesize de novo cytokines and chemokines important in the amplification of the inflammatory response. One of the most prominent triggers of inflammatory responses is the cytokine TNFα. However, the intracellular signaling cascades triggered by TNFα are not fully understood. In this study we investigated the roles of SPHK on the TNFα-triggered responses on human primary monocytes. We show that TNFα rapidly triggers S1P generation and activation of SPHK. Moreover, our data shows that SPHK1 is the isoform activated by TNFα, and plays an essential role on the TNFα-triggered intracellular Ca2+ signals, degranulation, cytokine production, and activation of NFκB, thus suggesting a pivotal role for SPHK1 on the proinflammatory responses triggered by TNFα. J. Cell. Physiol. © 2006 Wiley-Liss, Inc.