Six frail male outpatients 70 years and older deemed at risk for fall, but not suffering from serious medical problems nor receiving immune-altering drugs, received an exercise intervention of increasing strenuousness for 60 minutes 3 times a week for 3 months in comparison with 7 controls having no intervention. Psychosocial and immunologic assessments were made at baseline (Time 1), and after 6 (Time 2) and 12 (Time 3) weeks of physical conditioning. Cytotoxic activity of natural killer (NK) cells significantly decreased during the course of the study, in spite of transient exercise-induced increases at times 2 and 3. Despite the many known benefits of exercise, this report suggests its possible adverse effects on NK cell cytotoxicity in the very frail elderly. Mild overexertion in frail old people may be clinically significant in view of the now recognized role of NK cells in the prevention of metastasis.