The effects, synthesis, and release of cytokines show diurnal patterns. We used recombinant human interleukin-1alpha radioactively labeled with 125I (I-IL) to determine whether its uptake by brain, spinal cord, testis and muscle showed a diurnal rhythm when tested every 4 h in mice. Each tissue showed statistically significant diurnal variation in their uptakes of I-IL ranging from a nearly 10-fold difference for the spinal cord to less than a 2-fold difference for muscle. All nadirs occurred at either 04.00 or 24.00 h and all peaks at 08.00 or 12.00 h. The pharmacokinetics of intravenously injected I-IL did not show any significant variations in blood. Recombinant human tumor necrosis factor-alpha, which does not cross the blood-brain barrier, did not show a diurnal rhythm in its uptake by any of these tissues. This diurnal variation in the rate of uptake of cytokines by tissues could underlie differences in potency when given at different times of the day.