A number of cases of pulmonary injury by use of aerosolized surface coating products have been reported worldwide. The aerosol from a commercial alcohol-based nanofilm product (NFP) for coating of nonabsorbing surfaces was found to induce severe lung damage in a recent mouse bioassay. The NFP contained a 1H,1H,2H,2H-perfluorooctyl trialkoxysilane (POTS) and the effects were associated with the hydrolyzed forms of the silane; increase in hydrolyzation resulted in faster induction of compromised breathing and induction of lung damage. In this study, the impact of the solvent on the toxicity of POTS has been investigated. BALB/cA mice were exposed to aerosolized water-based NFPs containing POTS, and solutions of hydrolyzed POTS in methanol, ethanol, and 2-propanol, respectively. No acute respiratory effect was observed at exposure concentrations up to 110mg/m3 with an aqueous solution of POTS. However, exposure to POTS in methanol resulted in a decrease of the tidal volume—an effect that did not resolve within the recovery period. After 27min of exposure, the tidal volume had decreased by 25%, indicating partial alveolar collapse. For POTS in ethanol and 2-propanol, a 25% reduction of the tidal volume was observed after 13 and 9min, respectively; thus, the tidal volume was affected by increase of the chain length. This was confirmed in vitro by investigating lung surfactant function after addition of POTS in different solvents. The addition of vaporized methanol, 2-propanol, or acetone to aerosolized POTS in methanol further exacerbated the tidal volume reduction, demonstrating that the concentration of vaporized solvent participated in the toxicity of POTS.