We have investigated the effect of pain without tissue injury on natural killer (NK) cell activity in peripheral blood in humans and the effect of local anaesthesia on the response. Ten subjects were investigated during two sessions. First, self-controlled painful electric stimulation was applied to abdominal skin for 30 min to an intensity of 8 on a visual analogue scale (0-10). Next, the electric intensity profile was reproduced during local anaesthesia (mepivacaine 10 mg ml-1 s.c. to a total dose of 2.5 mg kg-1). NK cell cytotoxicity was measured using a 4-h 51Cr-release assay against K562 target cells. NK cell activity increased from mean 22 (SEM 4)% (baseline) to 35 (6)% and 36 (5)% after 15 and 30 min of painful stimulation, respectively (P < 0.02). A simultaneous increase in the number of CD56+ cells in peripheral blood during pain was found. Stimulation after local anaesthesia did not change either NK cell activity or number. Parallel and significant increases in concentrations of plasma epinephrine and serum cortisol were observed. These changes were abolished by local anaesthesia. We conclude that acute severe pain without tissue injury markedly increased NK cell cytotoxicity. Local anaesthesia completely abolished this immunological and hormonal response.