To delineate the immunoarchitecture of the normal human lacrimal gland, monoclonal antibodies that detect B- and T-lymphocyte, macrophage, and dendritic cell lineage, subset, and differentiation-associated antigens were used in combination with highly sensitive tissue-section immunoperoxidase techniques. Plasma cells, identified with monoclonal antibody OKT10, represented the predominant mononuclear cell population, accounting for 53.9% of all mononuclear cells present. A qualitative study of plasma cell cytoplasmic immunoglobulin heavy-chain expression in deparaffinized, formalin-fixed tissue sections showed that the vast majority of these plasma cells contained IgA. Rare plasma cells contained IgG, IgM, or IgD. T-cells, identified with monoclonal antibody OKT3, represented the second most common cell type in the normal human lacrimal gland, accounting for 40.3% of all mononuclear cells present. T cells were located predominantly in lymphocytic foci and singly in the interstitium. T8 antigen-positive (suppressor/cytotoxic) T cells predominated over T4 antigen-positive (helper) T cells, averaging 25.2 and 14.7%, respectively. The overall mean T4/T8 ratio was 0.56. T8 antigen-positive T cells were the most numerous cell population outside aggregates and follicles, being distributed almost equally between the acini and the ducts (49%) and the interstitium (51%). Only 16% of T4 antigen-positive cells preferred glands or ducts to the interstitium. B cells, identified with monoclonal antibody BL9, represented only 5.7% of all mononuclear cells present. B cells were exclusively found in the centers of primary and secondary follicles. The majority of the surface immunoglobulin-positive B cells expressed IgM, fewer expressed IgD, and still fewer expressed IgG or IgA. Rare LeuM1+ OKM1+ macrophages were present in the center of B-cell follicles, where rare OKT6+ dendritic cells and activated T cells (IL-2+) were also discovered. These results support the concept that the lacrimal gland belongs to the mucosa-associated lymphoid system.