We previously reported that inactive frail old (FO) subjects exhibit mitochondrial DNA damage and ETC dysfunction vs. physically active young and old (AO) subjects (Safdar et al, 2006). We now investigate whether these observations are associated with changes in oxidative stress, inflammation and a nuclear factor erythroid 2‐related factor 2 (Nrf2)‐mediated antioxidant response. Muscle biopsies were taken from the vastus lateralis of young (mean ± SD: 22 ± 2 y, n = 11), AO (70 ± 5 y, n = 10) and FO (65 ± 10 y, n = 12) subjects and analyzed for markers of oxidative stress (protein carbonyls) and inflammation (C‐reactive protein, CRP), SOD enzyme activity (Cu/Zn‐ and Mn‐ SOD), and protein content of an ETC element (COX, subunit I), antioxidant enzymes (GPx1 and catalase) and the phase II detoxification regulators Nrf2 and Keap1 (a negative regulator of Nrf2). FO and AO had 1.5 fold higher protein carbonyls vs. the young (P = 0.046), whereas FO had higher CRP vs. the young (4 fold, P < 0.001) and AO (1.8 fold, P = 0.043). Mn‐SOD, but not total‐ or Cu/Zn‐ SOD, activity was lower in the FO vs. the young and AO (P ≤ 0.03 for both). FO had higher catalase, but lower COX‐I, protein content vs. the young and AO (P ≤ 0.03 for both). Our novel finding is that AO had higher Nrf2 protein content vs. the young and FO (P ≤ 0.01 for both), and lower Keap1 protein content vs. the young only (P = 0.01). We conclude that the mitochondrial dysfunction observed in the FO is associated with an increase in oxidative stress and systemic inflammation, and dysregulation of Nrf2‐mediated antioxidant response. (Funded by CIHR)