Immune defense capacity differs between men and women. Whereas men are more prone to infection and sepsis, women more commonly develop autoimmune diseases. We investigated the difference in cytokine secretion between males and females in response to different immune stimuli. Whole blood from 154 healthy volunteers (age 24 +/- 5.2; 82 females, 72 males) was collected within 2 h on 2 consecutive days. Blood from males produced significantly more tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and IL-8 than blood from females in response to a high concentration of either lipopolysaccharide (LPS) or lipoteichoic acid (LTA), whereas IL-10 and interferon-gamma (IFN-gamma) secretion did not differ. Normalization of cytokine measurement to individual monocyte counts cancelled these differences for all parameters except TNF-alpha. Stimulation with a lower concentration of LPS (100 pg/mL) produced even stronger differences in cytokine release, which were not cancelled by normalization to the producing cells. The coefficients of variation (CV) of the LPS-induced and LTA-induced cytokine responses were higher in blood from women than men for all parameters and stimuli measured. Thus, the stronger innate immune response of males in comparison to females appears to stem not only from a difference in monocyte counts but also from the steepness of the response curve.