Thymic epithelial cells express major histocompatibility complex (MHC) class II and are involved in T-cell ontogeny. In these cells, MHC class II-associated invariant chain (CD74) is involved in antigen presentation during T-cell selection. We studied a range of thymic epithelial neoplasms for CD74 expression by neoplastic epithelial cells to determine whether such expression correlates with MHC class II expression and tumor type. Sixty-four thymic epithelial neoplasms (27 cases of benign thymoma, 20 cases of invasive thymoma, and 17 cases of true thymic carcinoma) were studied for neoplastic epithelial cell expression of CD74 and MHC class II molecules by immunohistochemical staining of paraffin-embedded tissue. Neoplastic epithelial cells in 88% of thymic carcinomas (15/17), 70% of invasive thymomas (14/20), but only 33% of benign thymomas (9/27) were immunoreactive for CD74. A subset of CD74-positive neoplasms was positive for MHC class II as well, with higher relative rates of dual positivity in more aggressive neoplasms. In addition, specific histologic subtypes of thymic epithelial neoplasms displayed differing patterns of CD74 positivity. Based on these findings, CD74 and MHC class II are useful markers for the classification of thymic epithelial neoplasms.