Activation-induced CD154 expression on CD4 T cells is prolonged in systemic lupus erythematosus, but the mechanism(s) for its dysregulation are unknown. The studies reported herein demonstrate that interleukin-15 (IL-15) is capable of prolonging CD154 expression on phytohemagglutinin (PHA)-activated CD4 T cells. As IL-15 signals through signal transducer and activator of transcription 5 (STAT5), predicted STAT5 binding sites in the human CD154 transcriptional promoter were identified, and STAT5 binding to the proximal CD154 promoter in vitro and in vivo following primary CD4 T-cell activation was demonstrated. Moreover, overexpression of wild-type STAT5 in primary human CD4 T cells augmented CD154 transcription, whereas overexpression of a dominant-negative (DN) STAT5 protein inhibited CD154 transcription. Mutation of the most proximal STAT5 binding site in the CD154 promoter resulted in diminished DNA binding and reduced CD154 transcriptional activity. Interestingly, STAT5-specific small interfering RNA inhibited CD154 surface expression at 48 but not 24 h after T-cell activation. Thus, these findings provide some of the first evidence to support a possible mechanistic link to explain how the overexpression of IL-15 observed in lupus patients may be involved in the prolonged expression of CD154 that has also been observed on lupus CD4 T cells.