Cytochrome p450 enzymes (Cyps) are major phase-I xenobiotic-metabolizing enzymes. Cyps are regulated by many environmental chemicals and drugs. However, knowledge about regulation of Cyps by perfluorocarboxylic acids (PFCAs), which are persistent in the environment, is limited. Two days after a single i.p. administration (50 mg/kg) of perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) increased mRNA expression of Cyp2B10 (20-fold), 3A11 (two-fold), and 4A14 (32-fold), but not Cyp1A1/2 in mouse livers. PFDA and PFOA also markedly increased protein expression of Cyp2B (50-fold) and 4A (10-fold). PFDA increased Cyp4A14 mRNA expression at relatively low doses (0.5 mg/kg), but increased Cyp2B10 mRNA expression only at high doses (> 20 mg/kg). By using constitutive androstane receptor (CAR)-, pregnane-X receptor (PXR)-, peroxisome proliferator-activated receptor alpha (PPAR)-alpha-, and farnesoid X receptor-null mouse models, PPAR-alpha and CAR were shown to play central roles in the induction of Cyps by PFDA. Specifically, PFDA increased Cyp4A14 mRNA expression in wild-type (WT) mice, but much less in PPAR-alpha-null mice. PFDA increased Cyp2B10 mRNA expression in WT mice, but not in CAR-null mice. In addition, PFDA increased mRNA expression and nuclear translocation of the transcription factor CAR. Therefore, the current studies provide important insight into understanding the regulatory mechanisms initiated by PFCAs, and may help to better predict and understand the toxicokinetics and toxicodynamics of various PFCAs. In conclusion, PFCAs increased Cyp2B10 and 4A14 expression by activating PPAR-alpha and CAR nuclear receptors, respectively. PPAR-alpha is activated at much lower doses of PFDA than CAR.