Sleep is commonly considered to support immune defense. The underlying sleep‐immune interaction appears to rely critically on cytokines, like interleukin‐6 (IL‐6), that combine effects on immune and neuronal functions. The IL‐6 signal is conveyed in two ways: it stimulates a restricted group of (mostly immune) cells via membrane‐bound IL‐6 receptors (mIL‐6R) by forming a complex with soluble IL‐6R (sIL‐6R), and it stimulates (via membrane‐bound gp130) a great variety of other cell types—a process termed trans ‐signaling. Focusing on the receptor side of IL‐6 signaling, we examined the effect of sleep on sIL‐6R plasma concentrations, mIL‐6R expression, plasma sgp130, and numbers of IL‐6‐producing monocytes in healthy humans who were tested during a regular sleep‐wake cycle and 24 h of wakefulness while blood was sampled repeatedly. Sleep strongly enhanced concentrations of sIL‐6R, exceeding wake levels by 70% at the end of sleep. This rise was due to an increase in the PC (proteolytic cleavage) rather than the DS (differentially spliced) variant of sIL‐6R. Sleep did not affect IL‐6‐producing monocytes, mIL‐6R density, or sgp130 concentrations. The selective increase in sIL‐6R implicates an enhanced trans ‐signaling capacity whereby sleep distinctly widens the profile of IL‐6 actions, enabling an integrated influence on brain and peripheral organs.—Dimitrov, S., Lange, T., Benedict, C., Nowell, M. A., Jones, S. A., Scheller, J., Rose‐John, S., Born, J. Sleep enhances IL‐6 trans‐signaling in humans. FASEB J. 20, E1599 –E1609 (2006)