Ascent to and living under the microgravity conditions found during spaceflight is an unfamiliar environment for humans. The adaptation to the space environment may be perceived by the body as a stress. On the ground, stress results in increased cytokine activity. The objective of this study was to determine whether spaceflight is associated with increased cytokine activity. The mean daily urinary interleukin-6 (IL-6) excretion rate was measured on 24-h urine pools collected from four payload crew members from 11 days before launch to 7 days after landing for a total of 27 days. In addition, in-flight data were obtained from two orbiter crew members. The experiment was conducted before, during, and after the 1991 9.5-day SLS-1 (Columbia) space shuttle mission. Dietary intake and urine output were monitored continuously for the 27-day period for the four payload crew. Results are as follows: 1) urinary IL-6 excretion and cortisol excretion were increased on the 1st day of spaceflight, suggesting an acute-phase response; 2) elevated levels of IL-6 were not found in the urine on any other days before or during flight; and 3) two of the subjects had markedly increased IL-6 excretion rates after landing.