In a recent study we found that 4 weeks of human experimental forearm immobilization induced hypersensitivity to mechanical and cold stimuli and a higher skin temperature on the immobilized hand. Identical findings are reported in immobilization studies in rats where increased substance P signaling is suggested to play a central role. Capsaicin releases substance P from axon collaterals in the periphery initiating vasodilatation and plasma extravasation. The effect of immobilization on capsaicin-induced responses is, however, not known. Therefore, the present study examined the effect of experimental forearm immobilization on capsaicin-induced pain and flare responses in healthy subjects. Twenty-seven human volunteers were exposed to 4 weeks of scaphoid cast immobilization of the left forearm. Before and after immobilization, skin temperature and blood flow were measured at the thumbs of both hands during 5 min of rest. Subjects then received topical capsaicin (5%) randomly on the dorsum of the right and left hands. Time to sensory detection of capsaicin and pain onset was significantly increased on the immobilized left hand. Immobilization significantly reduced capsaicin-evoked pain, neurogenic flare area, and skin blood flow (perfusion units), and the reduced capsaicin-evoked pain was significantly correlated to an increase in peripheral skin temperature but not to skin blood flow. The correlation between reduced capsaicin-evoked pain and increased skin temperature suggests an increased substance P release while the delayed onset and diminished magnitude of capsaicin-induced pain may be due to reduced penetration of capsaicin into the epidermis.