Human mannose-binding lectin (MBL) is encoded by the MBL2 gene and is a key player in innate immunity. However, the mechanism of the transcriptional regulation of MBL2 is largely unknown. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that play an important role in a number of biological responses, including lipid homeostasis, immune function and adipogenesis. In this study, we showed that PPARα and PPARγ up-regulate the expression of human MBL2. Using a luciferase assay, electrophoretic mobility-shift assay and chromatin immunoprecipitation assay, we demonstrated that PPARs regulate the expression of human MBL2 via the peroxisome proliferator responsive element (PPRE). On the other hand, MBL2 mRNA expression was not affected by the PPARα ligand both in vivo in rat liver and in vitro in rat H4IIE hepatoma cells. Thus, there is a species difference in regulation of MBL2 gene expression by PPARs between humans and rodents. We also show that the species differences in response to PPAR could be due in part to sequence-specific differences in the PPRE in the promoter region of MBL2. These results indicate that human, but not rat, MBL2 expression is regulated by PPARs via a PPRE.