The control of mRNA stability is crucial to the regulation of cytokine expression. We describe here a novel, potent destabilizing element found in the 3' untranslated region of granulocyte colony-stimulating factor mRNA. This element, which appears to require at least one stem-loop structure, we term the stem-loop destabilizing element (SLDE). Functionally equivalent elements appear to also exist in the interleukin 2 and interleukin 6 mRNAs. The SLDE is functionally distinct from the A+U-rich elements, which are also present in these and other cytokine mRNAs, because it destabilizes a chimeric mRNA in a tumor cell line in which A+U-rich elements do not function. In addition, the effect of the SLDE is insensitive to calcium ionophore and is therefore regulated independently of A+U destabilizing elements. The existence of two distinct mRNA-destabilizing elements provides an additional mechanism for the differential regulation of cytokine expression.