Natural killer (NK) cell activity was measured blindly in vitro with blood specimens from 50 healthy individuals and 20 patients with clinically defined chronic fatigue immune dysfunction syndrome (CFIDS) who met the criteria established by the Centers for Disease Control and Prevention (Atlanta). In accordance with a group scoring system of 1-10 points, with 10 being the most severe clinical status, the patient population was stratified into three clinical groups: A (> 7 points), B (5-7 points), and C (< 5 points). NK cell activity was assessed by the number of lytic units (LU), which for the 50 healthy controls varied between 20 and 250 (50%, 20-50 LU; 32%, 51-100 LU; 6%, 101-130 LU; and 12%, > 150 LU). In none of the 20 patients with CFIDS was the NK cell activity > 100 LU. For group C, the 10 patients stratified as having the least severe clinical condition, the measure was 61.0 +/- 21.7 LU; for group B (more severe, n = 7), it was 18.3 +/- 7.3 LU; and for group A (most severe, n = 3), it was 8.0 +/- 5.3 LU. These data suggest a correlation between low levels of NK cell activity and severity of CFIDS, which, if it is confirmed by additional studies of larger groups, might be useful for subgrouping patients and monitoring therapy and/or the progression of CFIDS.