Development of dry eye disease often occurs in individuals with autoimmune disorders such as Sjögren's syndrome. The cause of dry eye in these patients is thought to be due, at least in part, to lymphocytic infiltration of the lacrimal glands, with subsequent loss of secretion of the aqueous component of tear film. How this lymphocytic infiltration leads to loss of secretion is not fully understood. We have previously shown that the proinflammatory cytokine, interleukin-1beta (IL-1beta), can stimulate the production of nitric oxide (NO) in cultured lacrimal gland acinar cells. It is possible that IL-1beta, produced by the infiltrating macrophages, stimulates production of inducible nitric oxide synthase (iNOS), and subsequently excessive production of NO. Peroxynitrate and other radical byproducts associated with excessive synthesis of NO may be detrimental to normal function of the lacrimal gland. Here we show that the peroxisome proliferator-activated receptor (PPAR)alpha and gamma agonists can inhibit NO production in cultured lacrimal gland acinar cells. Further, this is accomplished without loss of iNOS expression or tetrahydrobiopterin. These data suggest that the use of ointments or eye drops containing these PPAR agonists may provide an effective therapeutic intervention for the prevention of dry eye in Sjögren's syndrome patients.