Transient receptor potential vanilloid 1 (TRPV1) is a Ca 2+-permeable cation channel activated by a variety of physicochemical stimuli. The effect of hypoxia (PO 2+ , 3%) on rat TRPV1 overexpressed in HEK293T has been studied. The basal TRPV1 current (I TRPV1) was partly activated by hypoxia, whereas capsaicin-induced TRPV1 (I TRPV1,Cap) was attenuated. Such changes were also suggested from hypoxia- and capsaicin-induced Ca 2+ Signals in TRPV1-expressing cells. Regarding plausible changes of reactive oxygen species (ROS) under hypoxia, the effects of antioxidants, vitamin C and tiron, as membrane-impermeable and-permeable, respectively, were tested. Both I TRPV1 and I TRPV1,Cap were increased by vitamin C, while only I TRPV1 was slightly increased by tiron. The hypoxic inhibition of I TRPV1,Cap was still persistent under hypoxia/ vitamin C. Interestingly, hypoxia/tiron strongly inhibited both I TRPV1 and I TRPV1,Cap. Also, with vitamin C applied through a pipette solution, hypoxia inhibited I TRPV1 and I TRPV1,Cap. In contrast, hypoxia and hypoxia/tiron had no effect on the I TRPV1 induced by acid (pH 6.2, I TRPV1,Acid). Taken together, hypoxia partly activated TRPV1 while it decreased their sensitivity to capsaicin. Putative changes of ROS under hypoxia might underlie the side-specific effects of ROS on TRPV1: inhibitory at the extracellular and stimulatory at the intracellular side, respectively. The differential effects of hypoxia on I TRPV1,Cap and I TRPV1,Acid suggested that the intracellular ROS increase might attenuate the pharmacological potency of capsaicin.