Nuclear factor-E2–related factor 2 (Nrf2) is essential for the antioxidant effects of sevoflurane preconditioning (SPC). Nrf2 mutation abolished the increased antioxidant enzyme expression (A, manganese superoxide dismutase [Mn-SOD]; B, thioredoxin-1 [Trx1]; and C, nicotinamide adenine dinucleotide phosphate quinolone oxidoreductase-1 [NQO1]) induced by SPC (n = 6 for each group; *#P < 0.05 vs. the wild-type [WT]-ischemia/reperfusion [I/R] group, &P < 0.05 vs. the WT-sevo plus I/R group). Knockout of Nrf2 abolished the down-regulating effect of SPC on the generation of oxidative products (D, malondialdehyde [MDA]; E, 4-hydroxynonenal [4-HNE]; F, carbonyl protein; G, 8-hydroxy-2-deoxyguanosine [8-OHdG]; and H, reactive oxygen species [ROS]; n = 6; *P < 0.05 and **P < 0.01 vs. the WT-sham group; #&P < 0.05 vs. the WT-I/R group, $P < 0.05 and $$P < 0.01 vs. the WT-sevo plus I/R group). All data were expressed as mean ± SD. One-way ANOVA with Tukey post hoc test was used for statistical analysis. Nrf2^−/− = Nrf2 knockout; NS = no statistical significance between the Nrf2^−/−-I/R group and the Nrf2^−/−-sevo plus I/R group.