Plasma cell neoplasms are common hematopoietic malignancies that recently have been shown to be driven by specific genetic events. In the past decade, immunophenotyping by flow cytometry has become an important tool in the characterization of plasma cells. However, the clinical and prognostic significance of antigenic expression remains unclear. We analyzed 102 cases of plasma cell neoplasm by flow cytometric immunophenotyping for expression of CD56 and CD117 and correlated the results with immunohistochemical and cytogenetic findings. Expression of CD56 and CD117 was associated with hyperdiploidy and the absence of CD117 expression was associated with different immunoglobulin heavy chain gene (IGH) translocations. Assessment of CD117 expression on neoplastic plasma cells by flow cytometry is superior to immunohistochemistry. Simultaneous assessment of CD56 and CD117 expression by flow cytometry is a sensitive method for diagnostic evaluation of plasma cell neoplasms, and furthermore may function as a rapid adjunctive test providing independent prognostic information in the absence of cytogenetic data.