CD138 has been considered to be strongly expressed in multiple myeloma cells. However, CD138⁺ cells were decreased in some patients during the course of treatment. To clarify the clinical significance of this finding, we evaluated the correlations of CD138 levels with laboratory data employing flow cytometry. We found that CD138⁺ cells were decreased in 12 patients during treatment and were retained in the remaining 105 patients throughout their clinical courses. For nine (75%) patients in the CD138⁺ cells reduced group, median survival time was 25 months after the reduction in CD138⁺ cells was detected, and all nine died of myeloma. Furthermore, extramedullary lesions and specific cytogenetic abnormalities [del(17p), t(4;14), amplification of c-MYC] were observed in some patients when the number of CD138⁺ cells started to decrease. Interestingly, 2 of 3 patients who survived until the end of observation period showed re-increase in their CD138⁺ levels. Taking these observations together, it is unclear whether reduction of the number of CD138⁺ cells is associated with a poor prognosis and resistance to drugs. However, if treatment does not produce a reincrease in CD138⁺ levels, long term survival might be difficult to achieve.