1. In normal non-exercised skeletal muscles in mice, the activity of histidine decarboxylase (HDC), the enzyme which forms histamine, was very low. 2. HDC activity in the quadriceps femoris muscle was markedly elevated following contractions evoked by even a few minutes of direct electrical stimulation, peaking at 8-12 h following contraction lasting 10 min, and gradually decreasing during the 24 h following contraction. The elevation in HDC activity depended on the duration and strength of stimulation. 3. Direct electrical stimulation induced a quantitatively similar elevation of HDC activity in the muscles of mast-cell-deficient mice (W/Wv mice). 4. Prolonged walking at a speed of 6 m min-1 for up to 6 h with a 30 min rest period at 3 h also elevated muscle HDC activity, the magnitude of the elevation being related to the duration of the walking. Repeated exercise (training) for several days diminished the elevation of muscle HDC activity induced by walking. In contrast, starvation augmented the elevation of muscle HDC activity induced by walking. 5. Intraperitoneal injection of interleukin-1beta (IL-1beta) also elevated muscle HDC activity in a dose-dependent manner, as little as 1 microg kg-1 of IL-1 producing a significant elevation of muscle HDC activity. 6. IL-1beta was immunohistochemically detected in normal non-exercised quadriceps femoris muscle. We could not detect a significant increase in IL-1beta after exercise in the muscle or in serum: it may be below the level of detection. 7. On the basis of these results, together with those reported previously and the known actions of histamine, we propose that an elevation of HDC activity and generation of histamine occur in skeletal muscle following muscle contraction possibly as a result of induction by IL-1beta and that the histamine may be involved in fatigue in skeletal muscle as part of a defence mechanism preventing damage to the muscle.