The two-pore domain K⁺ channel TASK-1 plays an important role in various cell types including neurons and cardiac muscle. The expression of TASK-1 channels at the cell surface is subject to transcriptional and posttranslational regulation. Using several in vitro and in vivo protein-protein interaction assays we found that the p11 protein, also denoted S100A10, specifically interacts with a 40 amino acid region in the proximal C-terminus of TASK-1. Surface expression of TASK-1 in Xenopus oocytes and HEK293 cells was strongly enhanced when the p11 interacting domain was removed. Attachment of the p11 interacting domain of TASK-1 to the cytosolic tail of the reporter protein CD8 caused retention/retrieval of the construct in the endoplasmic reticulum (ER). Attachment of the last 36 amino acids of p11 to CD8 also caused ER-localisation, which was probably mediated by a di-lysine based retention signal at the extreme C-terminus of p11. Imaging of EGFP-tagged TASK-1 in COS-7 cells revealed that wild-type TASK-1 was largely retained in the ER. Knockdown of p11 with specific siRNA enhanced trafficking of TASK-1 to the surface membrane. Our results suggest that binding of p11 to the proximal C-terminus of TASK-1 retards surface expression of the channel. Thus p11 may represent a cytosolic 'retention factor' that regulates ER export of TASK-1.