Titanium dioxide engineered nanoparticles (nano-TiO2) are widely used in the manufacturing of a number of products. Due to their size (<100nm), when inhaled they may be deposited in the distal lung regions and damage Clara cells. We investigated the mechanisms by which short-term (1-h) incubation of human airway Clara-like (H441) cells to nano-TiO2 (6nm in diameter) alters the ability of H441 cells to adhere to extracellular matrix. Our results show that 1h post-incubation, there was a 3-fold increase of extracellular H2O2, increased intracellular oxidative stress as demonstrated by 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) oxidation, and a 5-fold increase of phosphor-ERK1/2 as measured by Western blotting. These changes were accompanied by a 25% decrease of H441 adherence to fibronectin (p<0.05 compared to vehicle incubated H441 cells). Pretreatment with the ERK1/2 inhibitor U0126 for 3h, partially prevented this effect. In conclusion, short-term exposure of H441 cells to nano-TiO2 appears to reduce adherence to fibronectin due to oxidative stress and activation of ERK1/2. © 2012 Elsevier B.V.