CD5 antigen is present on all normal alpha beta T cells and some B cells. Human NK cells do not usually express CD5 antigen, but we found a novel subset of CD5LOW (low density of CD5) positive (CD5LOW+) natural killer cells (NK cells) in patients with multiple myeloma (MM) and plasmacytoma. To detect CD5LOW+NK cells, we examined the lymphocytes of 23 patients with MM and plasmacytoma by flow cytometry. Five out of 23 patients had CD5LOW+NK populations. These patients had many more NK cells than the other patients in the peripheral blood and bone marrow. The CD5LOW+NK cells had CD2, low density of CD8, CD16 and CD56, but no CD3, CD19, or CD20. Most of the CD5LOW+NK cells had HLA-DR, unlike the CD5-NK cells. Sorted CD5LOW+CD16+ populations were large granular lymphocytes (LGL). The CD5LOW+NK cells had some lytic activity on K562 cells in a 4-hour 51Cr release assay. Our results indicate that there is a novel subset of NK cells in some patients with MM and plasmacytoma and that CD5LOW+NK cells may be associated with NK cell activation.