Natural killer (NK) cells are implicated in the pathogenesis of multiple sclerosis (MS). Nine relapsing-remitting MS (RRMS) patients along with age, sex, and NK responder status matched controls were studied serially. Although the average NK cell functional activity (FA) was not significantly different between both groups, four clinical relapses in RRMS patients were associated with the development of 'novel' valleys in FA. These valleys are of greater depth and duration than cyclical valleys observed in both RRMS and controls, precede the onset of clinical attacks, and are observed in RRMS but not controls. In both RRMS and controls, cyclical peaks and valleys in FA are determined by the number of CD33+, CD3-CD56+, and to a lessor extent CD3+CD56+ cells capable of binding targets and inducing cell-mediated cytotoxicity (CMC). In contrast, 'novel' valleys in FA result from a reduction in the ability of CD3-CD56 + bound to targets to induce CMC. The results suggest that RRMS patients are at greater risk for clinical relapses during 'novel' valleys in FA. Furthermore, these valleys are the result of cells with a NK cell phenotype being unable to deliver a 'lethal' hit to targets. © 2003 Elsevier B.V. All rights reserved.