Background: Evaluation of clonal plasma cells (cPCs) in the bone marrow (BM) of multiple myeloma (MM) patients (pts) reveals two distinct cPC populations based on CD45 expression, i.e. CD45- and CD45+. We explored the prognostic significance of CD45 expression by cPCs in the BM of MM pts using flow cytometry. Methods: All MM pts seen at the Mayo Clinic, Rochester from 2009 to 2011 who had BM PCs evaluated by flow cytometry were included. For flow cytometry, a 6-color method was used with each sample stained with antibodies to CD45, CD19, CD38, CD138 and cytoplasmic Kappa and Lambda Ig light chains. Samples where > 20% of the cPCs detected expressed CD45 were classified as CD45+ and the rest were CD45-. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: There were 604 consecutive MM pts who had their BM PCs evaluated by flow cytometry. Of these pts, 156 were newly diagnosed and 448 were previously treated with systemic therapy. Among newly diagnosed pts, the median follow up was 42 mos and 41 pts (27%) had high risk disease by FISH. The median time to next therapy (TTNT) for pts in the CD45+ group was 12 mos (n = 26, 17%) versus 29 mos for pts in the CD45- group (n = 130, 83%) (P = 0.002). The median overall survival (OS) for pts in the CD45+ group was 23 mos versus not reached for the CD45- group (P < 0.001). Among previously treated pts, the median follow up was 44 mos and 45% had a prior ASCT. There were 240 previously treated pts that were actively relapsing at the time of their bone marrow analysis. The median OS for actively relapsing pts classified as CD45+ was 11 mos (n = 61, 14%) versus 29 mos (n = 386, 86%) for CD45- (P < 0.001). In a multivariable analysis, CD45+ status and PCLI > 3 were independent predictors of worse OS among the newly diagnosed and actively relapsing pts. Increasing age and elevated LDH were independent predictors of worse OS in newly diagnosed and actively relapsing pts, respectively. Conclusions: The presence of > 20% cPCs in the BM expressing CD45 appears to bear negative prognostic value in newly diagnosed and actively relapsing MM pts. This may be a surrogate for a more aggressive phenotype of MM.