While plasmacytosis is a common occurrence in early post-bone marrow transplantation biopsy specimens, the significance of plasma cells in such specimens from patients with multiple myeloma (MM) is unknown. We attempted to retrospectively determine, by morphologic assessment of plasma cell percentage, immunohistologic assessment of plasma cell light chain ratio (LCR), and correlation with clinical outcome, the prevalence and significance of plasmacytosis in the posttransplantation bone marrow biopsy specimens of 25 patients with MM who underwent autologous peripheral blood stem cell transplantation (PBSCT). No pre-PBSCT morphologic or immunologic characteristics were significantly associated with the post-PBSCT outcome in this group of patients. While 9% of all biopsy specimens and 25% of hypocellular biopsy specimens obtained during the first 60 days after the PBSCT contained more than 10% plasma cells, 34% of all biopsy specimens obtained during this period had elevated LCRs. The dominant light chain in all cases with high LCRs was the same as that of the original tumors, implying that these plasma cells represent a portion of the patients' original tumors. However, the presence of tumoral plasma cells during the early post-PBSCT period was not associated with outcome (P>.5 at 30 days and 60 days after transplantation). Histologic features of recurrent MM and elevated LCR occurring at day 90 or later are correlated with progression of disease (P=.02 and P=.0001, respectively). We conclude that the presence of tumoral plasma cells in the early post-PBSCT period likely represents residual tumor and should not be regarded as indicating imminent relapse, while the presence of tumor as assessed by histologic or immunohistochemical evaluation during the late post-PBSCT period should raise the concern of relapse and disease progression.