Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) modulates gene expression in response to oxidative damage in neurodegenerative diseases, including spinal cord injury (SCI). We noticed that activation of Nrf2 pathway persists for an extended time after clinically relevant contusion model of SCI. Injured Nrf2-/- mice were impaired in hindlimb function, exhibited increased atrophy, demyelination, and astrogliosis of the SC concomitant with altered expression of genes controlling apoptosis, inflammation, and neurotrophic factors suggesting the importance of Nrf2 for recovery. We used lentiviral gene transfer to increase Nrf2 expression and improve functional recovery after SCI. Although the transferred Nrf2 was expressed in neurons and astrocytes, we noticed hindlimb function impairment and elevated expression of pro-inflammatory cytokines as an adverse effect. These toxic effects were not reduced by including Nrf2 in the lentiviral vector. Augmenting the amount of delivered Nrf2 gene diminished toxic effects of the lentivirus, yet was not sufficient to improve functional recovery. Results of this study lead to the hypothesis that Nrf2 plays a crucial and multifaceted role in recovery from SCI, but even high overexpression of Nrf2 in injured SC may not offer extra benefit, providing protection only against lentivirus-induced toxicity that is manifested in the SC. Antioxid. Redox Signal. 20, 1313-1323.