The recently identified and cloned cytokine IL-15 shares many of the T-cell and B-cell stimulatory activities of IL-2 and utilizes the beta and gamma chains of the IL-2R for binding and signaling. The present report shows that, like IL-2, IL-15 in a concentration and time-dependent manner causes the release of sIL-2Ralpha from PHA-activated human peripheral blood mononuclear cells. This effect of IL-15 is largely direct and independent of IL-2. Blocking of the IL-2Rbeta chain with the antibody Mik-beta1 prevented the release of sIL-2Ralpha by IL-15 but not by IL-2. IL-7, another cytokine utilizing the gamma chain of the IL-2R, drove the release of sIL-2Ralpha as well. Several clinical conditions are associated with abnormal serum sIL-2Ralpha levels and are also monitored by the measurement of sIL-2Ralpha. The reason for sIL-2Ralpha release is not fully understood. In this study, IL-15, like IL-2 was shown to be a potent inducer of sIL-2Ralpha release in vitro.