Sjogren’s syndrome (SS) is a chronic autoimmune disease characterised by inflammation of the exocrine glands, specifically the salivary and lacrimal glands that produce saliva and tears, respectively. The immune-mediated attack on the salivary and lacrimal glands leads to the development of dry mouth and eyes, associated with lymphocytic infiltration of the tissues. Cell adhesion molecules play a key role in leucocyte trafficking into tissues and blockade of these molecules has been effective in other autoimmune conditions such as multiple sclerosis. Increased expression of adhesion molecules has been reported in SS. In this paper animals deficient in thrombospondin-1 (TSP-1) that develop features similar to SS, were treated with an antagonist to integrin α4, (GW559090) which has a high affinity for integrin α4β1 inhibiting the interaction with VCAM-1 and fibronectin. The results show that topical administration of GW559090 significantly reduced corneal barrier disruption as shown by fluorescein staining, reduced corneal expression of IL-1β, and an increase in goblet cell numbers compared to control untreated animals. The results for GW559090 were comparable to topical administration of dexamethasone. These results show that inhibition of migration of cells into ocular tissue may be effective in preventing progression of SS, and may be a new therapeutic option in humans with this disease.