This study is to investigate the effect of high altitude hypoxia on the activity and protein expression of CYP2C9 and CYP2C19.  Rats from plain (P) and rats with acute middle altitude hypoxia (AMH), chronic middle altitude hypoxia (CMH), acute high altitude hypoxia (AHH) and chronic high altitude hypoxia (CHH) were administered orally phenytoin sodium (PHT) and omeprazole (OMZ) to evaluate the activity of CYP2C9 and CYP2C19, separately.  The serum concentrations of PHT and metabolite 4'-hydroxyphenytoin (HPPH) at 12 h after treatment and the serum concentrations of OMZ and metabolite 5-hydroxy omeprazole (5-OHOMZ) at 3 h after treatment were determined by RP-HPLC.  The activity of CYP2C9 and CYP2C19 was evaluated by the ratio of HPPH to PHT and the ratio of 5-OHOMZ to OMZ, respectively.  The protein expressions of CYP2C9 and CYP2C19 were determined by ELISA method.  The activities of CYP2C9 (HPPH/PHT) in P, AMH, CMH, AHH and CHH were 0.67 ± 0.31, 0.75 ± 0.29, 0.76 ± 0.23, 0.79 ± 0.31 and 0.75 ± 0.18, respectively, and the activities of CYP2C19 (5-OHOMZ/OMZ) in P, AMH, CMH, AHH and CHH were 0.17 ± 0.06, 0.20 ± 0.10, 0.11 ± 0.05, 0.37 ± 0.13 and 0.19 ± 0.05, respectively.  The protein expressions of CYP2C9 in P, AMH, CMH, AHH and CHH were 4.20 ± 1.27, 3.95 ± 0.81, 3.93 ± 1.11, 4.32 ± 1.03 and 4.12 ± 0.86 ng·g⁻¹, respectively, and the protein expressions of CYP2C19 in P, AMH, CMH, AHH and CHH were 3.91 ± 1.82, 3.63 ± 2.07, 2.55 ± 0.85, 4.78 ± 2.37 and 3.51 ± 1.03 ng·g⁻¹, respectively.  The activities and protein expressions of CYP2C9 in AMH, CMH, AHH and CHH were not significantly different with those of P.  The protein expressions of CYP2C19 in AMH, CMH, AHH and CHH were not significantly different with those of P, but the activity of CYP2C19 in AHH was significantly higher than that of P.  This study found significant changes in the activity of CYP2C19 under the special environment of acute high altitude hypoxia.