Fourteen thymomas were studied by electron microscopy and immunohistochemistry. Based on the ultrastructure of the neoplastic epithelial cells in comparison with normal thymic epithelium, four cortical-, three mixed-, five medullary-, and two corpuscular-type tumors were categorized. Histologically the tumors of cortical type showed prominent lymphocytic infiltration, but scant interdigitating reticulum cells (IDCs) were demonstrated by immunoperoxidase method on paraffin sections with anti-S-100 protein antiserum. Fewer lymphocytes but more IDCs were present in the tumors of medullary and corpuscular types, although variable in those of mixed type. This corticomedullary difference among thymomas was confirmed in some of them by the immunoperoxidase method on frozen sections with monoclonal antibodies. The cortical-type tumors were HLA-DR positive in tumor cells and infiltrated predominantly with cortical thymocytes (OKT-6+, OKT-3-, both Leu 3a/3b+ and OKT-8+), whereas the medullary- and corpuscular-type tumors were HLA-DR positive primarily in IDCs but not in tumor cells and were infiltrated more with medullary thymocytes (OKT-6-, OKT-3+, either Leu 3a/3b+ or OKT-8+). The classification of thymomas based on neoplastic epithelial cells will serve to refine the traditional classification based on reactive lymphocytes.