The voltage-gated potassium channel Kv1.3 plays an important role in T lymphocytes, B lymphocytes and microglia, and it is an active target for pharmaceutical development for autoimmune and neuroinflammatory diseases. We used single particle cryo-EM to determine the structure of human Kv1.3 in complex with its accessory subunit KvBeta2.1. The structure was resolved at 3.4 Å average resolution and 3.1 Å resolution in the pore. The channel’s outer pore exhibits a remarkably different conformation from other potassium channels. The outer pore is wider, and potassium is missing from site 2. This widening is the direct result of Tyr447 in the selectivity filter adopting a position different from that in other potassium channels. The new position of Tyr447 is stabilized by its interaction with His451 at the outer entrance to the pore. An additional potassium ion just below the selectivity filter is coordinated by ordered water in the inner cavity and by carbonyl oxygens of the filter. The channel’s voltage-sensor is in the depolarized state and its inner gate is open. This distinct conformation may represent the C-type inactivated state of Kv1.3, which inactivates solely by the C-type inactivation mechanism. The structural underpinnings of C-type inactivation in voltage-gated potassium channels is controversial. Two models of C-type inactivation have been proposed, one involving constriction and the other dilation of the outer pore. Our structure is consistent with both the constriction and dilation models of C-type inactivation that has been proposed. Our data suggests that the structural mechanisms responsible for C-type inactivation may vary from channel to channel, with either dilation and/or constriction of the selectivity filter rendering it non-conducting.