Androgen therapy suppresses lymphocyte infiltration in, and improves the functional activity of, lacrimal glands in a female mouse model (MRL/Mp-lpr/lpr [MRL/lpr]) of Sjögren's syndrome. To extend these findings, the current investigation was designed to identify the cellular target(s) within lacrimal tissue that may mediate this androgen effect. In addition, we explored the endocrine regulation of androgen receptors in autoimmune lacrimal glands. Adult, female MRL/lpr mice were exposed systemically to vehicle, steroid hormones or immunosuppressive agents for varying time intervals after the onset of disease. Immediately before or after treatment, lacrimal glands were obtained and processed to determine the cellular distribution and nuclear density of androgen receptors by immunoperoxidase and image analysis techniques. Our findings demonstrated that: (1) androgen receptors exist almost exclusively within nuclei of acinar and ductal epithelial cells in lacrimal tissue of MRL/lpr mice; (2) androgen receptors are not detectable in the extensive lymphocytic populations that infiltrate the gland; (3) testosterone administration induces a significant increase in the number of androgen receptor-containing cells in, as well as the density of androgen receptors in epithelial cell nuclei of, lacrimal tissue; (4) hormone action is steroid-specific: administration of androgen analogues, but not estrogens, glucocorticoids or cyclophosphamide, stimulate the accumulation of androgen receptors; and (5) androgen receptor density is significantly reduced following the withdrawal of androgen therapy. These results show that epithelial cells, but not lymphocytes, are the androgen target cells in lacrimal tissue, and suggest that these cells may mediate the androgen-related immunosuppression and functional enhancement in lacrimal glands of autoimmune female mice. Our findings also demonstrate that androgens increase the expression of their own receptors in MRL/lpr lacrimal tissue.