Triple antibody flow cytometry was used to compare the populations of CD56+ effector cells in the peripheral circulation of 29 patients with relapsing multiple sclerosis (MS) and little disability who were exacerbation-free for over 2 months and 29 healthy control subjects. Populations were characterized by two panels of antibodies (CD8, CD16, CD56 and CD3, CD8, CD56), as well as by size or granularity. In the MS patients, mature natural killer (NK) cells (CD3-CD8-CD56+) of small size and low granularity were significantly reduced compared to normals (P(0.0003). The quantities of other effector cells (cytotoxic T lymphocytes, large granular lymphocytes and monocytes) were not different in MS patients compared to the control subjects. Also, we identified a previously unrecognized population of CD56+ monocytes (CD3-CD14+CD56+) in both the normal control subjects and the MS patients which would have been misclassified as NK cells using one or two antibody cytometry employed in previous studies.