The present study investigated the effects of diesel exhaust (DE) on an experimental model of bleomycin (BLM)-induced lung injury and fibrosis in mice. BLM was intravenously administered to both Nrf2(+/+) and Nrf2(-/-) C57BL/6J mice on day 0. The mice were exposed to DE for 56 days from 28 days before the BLM injection to 28 days after the BLM injection. Inhalation of DE induced significant inhibition of airway clearance function and the proinflammatory cytokine secretion in macrophages, an increase in neutrophils, and severe lung inflammatory injury, which were greater in Nrf2(-/-) mice than in Nrf2(+/+) mice. In contrast, inhalation of DE was observed to induce a greater increase of hydroxyproline content in the lung tissues and significantly higher pulmonary antioxidant enzyme mRNA expression in the Nrf2(+/+) mice than in Nrf2(-/-) mice. DE is an important risk factor, and Nrf2 regulates the risk of a DE inhalation induced immune response during BLM lung injury and fibrosis in mice.