T lymphocytes are exposed to hypoxia during their development and also when they migrate to hypoxic pathological sites such as tumors and wounds. Although hypoxia can affect T cell development and function, the mechanisms by which immune cells sense and respond to changes in O 2-availability are poorly understood. K+ channels encoded by the Kv1. 3 subtype of the voltage-dependent Kv1 gene family are highly expressed in lymphocytes and are involved in the control of membrane potential and cell function. In this study, we investigate the sensitivity of Kv1. 3 channels to hypoxia in freshly isolated human T lymphocytes and leukemic Jurkat T cells. Acute exposure to hypoxia (20 mmHg, 2 min) inhibits Kv1. 3 currents in both cell types by 20%. Prolonged exposure to hypoxia (1% O 2 for 24 h) selectively decreases Kv1. 3 protein levels in Jurkat T cells by 47%, but not Kvβ2 and SK2 Ca-activated K+ channel subunit levels. The decrease in Kv1. 3 protein levels occurs with no change in Kv1. 3 mRNA expression and is associated with a significant decrease in K+ current density. A decrease in Kv1. 3 polypeptide levels similar to that obtained during hypoxia is produced by Kv1. 3 channel blockage. Our results indicate that hypoxia produces acute and long-term inhibition of Kv1. 3 channels in T lymphocytes. This effect could account for the inhibition of lymphocyte proliferation during hypoxia. Indeed, we herein present evidence showing that hypoxia selectively inhibits TCR-mediated proliferation and that this inhibition is associated with a decrease in Kv1. 3 proteins.