Irritant-induced inflammation of the airways may aggravate respiratory allergy induced by chemical respiratory allergens. Therefore, it was studied whether airway irritation by sulfur dioxide (SO<sub>2</sub>) would enhance respiratory allergic reactions to trimellitic anhydride (TMA), using a rat model. Brown Norway (BN) rats were topically sensitized, subsequently exposed for a single time or repeatedly to 300ppm SO<sub>2</sub>, and challenged by inhalation to a distinctly irritating or minimally irritating concentration of TMA after the (last) SO<sub>2</sub> exposure. Repeated exposure to SO <sub>2</sub> alone reduced breathing frequency during exposure, and caused epithelial alterations including hyperplasia and squamous metaplasia, and infiltration of polymorphonuclear inflammatory cells into nasal tissues, larynx, trachea, and bronchi/bronchioli. Histopathological changes were less prominent after 1 day of SO<sub>2</sub> exposure. Repeated pre-exposure to SO<sub>2</sub> reduced the number of TMA-induced apnoeas, in an SO<sub>2</sub> exposure duration-dependent manner. This effect of SO<sub>2</sub> on TMA-induced functional allergic reactions (apnoeas) was distinct only when the TMA challenge concentration was not too irritating itself. Repeated pre-exposure to SO <sub>2</sub> reduced TMA-induced laryngeal ulceration, goblet-cell hyperplasia, and inflammation in the lungs in most animals, regardless of the TMA challenge concentration. The SO<sub>2</sub>-induced replacement of normal respiratory epithelium by less sensitive, squamous epithelium may offer an explanation for the, unexpected, reduced allergic manifestation. However in a few animals, SO<sub>2</sub> appeared to facilitate TMA-induced irritation, probably due to incomplete protection. Overall, SO<sub>2</sub> exposure of TMA-sensitized rats reduced TMA-related allergic respiratory responses in most animals.