Undifferentiated tumors and hematolymphoid neoplasms can be diagnostically challenging due to potential overlap of morphologic features and variant antigen expression. PAX-5, a transcription factor expressed throughout B-cell maturation, is detected in most B-cell neoplasms including those that lack expression of mature B-cell markers, such as classical Hodgkin lymphoma (cHL), B-lymphoblastic leukemia and B-cell lymphomas following rituximab therapy. The lack of PAX-5 expression in most CD30-positive non-hematopoietic malignancies (embryonal carcinoma and seminoma) and T-cell lymphomas, such as anaplastic large cell lymphoma (ALCL), suggests that the absence of PAX-5 may be used to confirm non-B-cell lineage. The goal of this study was to retrospectively assess PAX-5 immunoreactivity in diagnostic samples of hematolymphoid and other non-hematopoietic malignancies.