Progression of multiple myeloma (MM) from intramedullary to extramedullary sites heralds an aggressive phase of the disease but to the best of our knowledge, biologic factors have not been studied in paired biopsies from medullary and extramedullary sites. In this study, we immunostained paired bone marrow and extramedullary biopsies from 12 cases of MM for p53, CD56 and MIB-1 (proliferative index). In addition, 22 cases of extramedullary plasmacytoma (EMP) without bone marrow involvement were included as a control group. p53 nuclear accumulations were detected in myeloma cells derived from the extramedullary sites in 9 (75%) of the 12 cases, whereas only 1 of (8%) 12 bone marrow myeloma specimens expressed p53 (P = 0.003). p53 expression was also more prevalent in extramedullary sites of MM than EMP (75% vs. 18%, P = 0.003). There was no significant difference in CD56 expression between intramedullary and extramedullary MM (17% vs. 33%, P = 0.64), or between intramedullary MM and EMP (17% vs. 38%, P = 0.25). The MIB-1 proliferation index increased significantly as plasma cells migrated from the bone marrow microenvironment to extramedullary sites (P = 0.0001). Our data indicates that p53 nuclear expression but not CD56 expression, along with increased proliferation index is associated with disease progression from intramedullary to extramedullary sites in MM.