In the present study, we analyzed the cell cycle distribution of bone marrow (BM) cells in 120 untreated multiple myeloma patients using a DNA/CD38 double-staining technique at flow cytometry in which plasma cells (PCs) can be clearly discriminated from residual BM cells based on their CD38 expression. This approach allows us to determine the proliferative activity of both PCs and residual normal BM cells. The percentage of S-phase cells in the myelomatous population was found to be significantly lower than that of the residual normal BM cells (P < .001). Regarding the proliferative activity of myelomatous cells, patients with a high number of S-phase PCs (> 3%) showed a significantly (P < .05) increased incidence of anemia and hypercalcemia; higher values of beta 2-microglobulin (beta 2M), urea, and creatinine; and higher numbers of peripheral blood natural killer cells, as well as a poor prognosis as assessed both by response duration and overall survival. With respect to the residual BM normal fraction, a low proliferative activity was significantly (P < .05) associated with the presence of anemia and neutropenia together with increased numbers of BM PCs, a higher incidence of Bence Jones myelomas, and DNA diploidy. Multivariate analysis showed that the number of S-phase PCs was the most important independent prognostic factor, allowing us to discriminate two subgroups of patients with different prognoses, even within the same clinical stage. Moreover, the S-phase PCs, together with beta 2M, age, and performance status, represent the best combination of disease characteristics for stratifying patients according to prognosis and allow the establishment of a simple and powerful staging system for multiple myeloma patients. In addition, this classification can be used for planning treatment in patients who are candidates for transplantation.