The peroxisome proliferator activated receptor α (PPAR) is a member of the steroid/hormone receptor superfamily that mediates the peroxisome proliferator-dependent transcriptional activation of genes encoding several peroxisomal and microsomal enzymes as well as peroxisome proliferation. Human liver is refractory to the pathological effects of peroxisome proliferators that are seen in mice. With the use of RNase protection assays, the ratio of hepatic PPARα mRNA to β-actin mRNA was found to be I order of magnitude lower in humans than that observed in mice. In addition, the isolation of human cDNA for PPARα that does not encode a functional PPAR because it lacks exon 6 as a result of alternate RNA splicing suggested that this process might also diminish the expression of PPARα. RNase protection analysis of total RNA revealed the presence of splice variants lacking exon 6 at significant levels in all 10 human liver samples examined. Supershift analysis using the CYP4A6-Z peroxisome proliferator response element and antisera specific for PPARα revealed easily detectable amounts of PPARα DNA binding activity in mouse liver lysates, whereas human liver lysates contained >10-fold lower amounts of PPAR2α DNA binding activity. In contrast to mouse lysates, the amount of PPARα binding in human lysates was generally less than that of other unidentified proteins. These results suggest that although humans retain the coding potential for a functional receptor, the low levels of PPARα expression in liver may be insufficient to compete effectively with other proteins that bind to peroxisome proliferator response elements.