Extracellular-superoxide dismutase (EC-SOD) is the major SOD isozyme in the blood vessel walls and may be important for antioxidant capability of the vascular walls. Expression of EC-SOD is known to be regulated by numerous substances such as cytokines and vasoactive factors. Recently, we found that the plasma EC-SOD levels in type 2 diabetic patients were significantly and inversely related to indices of insulin resistance, whereas they were strongly and positively related to adiponectin. Administration of pioglitazone significantly increased the plasma level of EC-SOD and adiponectin. Transcription factors such as CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptors (PPARs) are known to regulate genes associated with insulin resistance. The aim of this study was to assess the contribution of these transcription factors on the EC-SOD level. We found that a C/EBPbeta enhancer, prolactin, significantly induced the EC-SOD mRNA and protein levels in cultured fibroblast cell lines, but PPARgamma ligands, pioglitazone and other thiazolidinedione agents did not. Deletion analysis of the EC-SOD promoter-luciferase construct showed that an important element responsible for prolactin is located between -242 and -178 in the promoter region of the EC-SOD gene in which a known C/EBPbeta-binding site is located. Increasing the EC-SOD expression by treatment with ligands of transcription factors might be one approach to ameliorate the pathological conditions of insulin resistance.