Primary non-Hodgkin's lymphomas of bone (PNHLB) is a rare form of extranodal lymphoma. Many studies have reported the clinical, radiologic, and histopathologic characteristics of PNHLB; however, their molecular features have not been well studied. In this report, we present the immunophenotypic and molecular characteristics of 20 primary large B-cell lymphoma (PLBCL) of bone from 20 adults. Most demonstrated centroblastic morphology, with the majority exhibiting nuclear multilobation. One case (5%) demonstrated anaplastic features with strong CD30 expression but was ALK-1 negative. BCL-6 expression was seen in 6 of 20 cases, and strong p53 protein expression was seen in 11 of 20 (55%) cases. The majority of cases analyzed (13/18 = 72%) demonstrated a clonal B-cell process by IgH gene rearrangement studies. Of the five cases that did not demonstrate a clonal population, two expressed BCL-6 protein. No cases demonstrated a bcl-2/JH rearrangement, but BCL-2 protein expression was seen in 11 of 20 (55%) cases. In summary, primary lymphoma of bone is largely a non-Hodgkin's lymphoma of large B-cell type. Our studies demonstrate that p53 and BCL-2 expression may play a role in the pathogenesis of PLCBL of bone. In addition, a subset of the cases are of putative germinal center B-cell origin based on the expression of BCL-6 protein and may be genetically distinct from follicle center lymphomas. The results provide evidence for molecular heterogeneity within primary large B-cell lymphomas of bone.