IL-15 promotes the growth of T cells and shares properties of IL-2. IL-2 is produced exclusively by T cells, while IL-15 message is expressed by a variety of tissues. However, it has been difficult to demonstrate IL-15 in the supernatants of many cells that express message for this cytokine. This suggests that IL-15 production is regulated by post-transcriptional controls. In this study, we cloned three types of murine IL-15 cDNA isoforms generated by alternative splicing and compared the translational efficiency among these isoforms. The translational efficiency of isoforms with alternative exon 5 containing another 3' splice site was significantly higher than that of IL-15 cDNA with originally described exon 5, which is generated by internal splicing of alternative exon 5. The translation product of the isoform containing alternative exon 5 has a shorter open reading frame due to stop codons in additional sequence, followed by a new AUG codon, and displays a shorter leader sequence. The shorter isoform of the IL-15 was detected in peritoneal macrophages stimulated with IFN-gamma and LPS, which expressed an abundant level of alternative exon 5. These results suggest that normal IL-15 production in stimulated macrophages is regulated by splicing of alternative exon 5.