Hodgkin lymphoma (HL) was shown to be a B-cell malignancy using polymerase chain reaction (PCR) clonality studies of microdissected Reed-Sternberg cells. While methods for the detection of B-cell clonality could aid in the diagnosis of HL, microdissection is not practical in most clinical settings. We assessed the standardized BIOMED-2 IGH and IGK PCR primers for the detection of clonality using 50 consecutively diagnosed formalin-fixed, paraffin-embedded (FFPE) classic HL specimens. Without microdissection, clonality was detected in 23 of 47 assessable cases. The IGK assay was significantly more sensitive than the IGH assay (18 vs 10 positive results). These data and 2 representative cases demonstrate that PCR-based B-cell clonality assays have usefulness when the histologic differential diagnosis of an FFPE specimen includes classic HL.