DeltaF508 CFTR can be functionally restored in the plasma membrane by exposure of the cell to lower temperature. However, restored DeltaF508 CFTR has a much shorter half-life than normal. We studied whether NHERF1, which binds to the PDZ motif of CFTR, might be a critical mediator in the turnover of DeltaF508 CFTR from the cell surface. We used RNAi to reduce the expression of NHERF1 in human airway epithelial cells. Knockdown of NHERF1 reversibly reduces surface expression of WT-CFTR without altering its total expression. As expected, temperature correction increased mature C band DeltaF508 CFTR (rDeltaF508) but unexpectedly allowed immature B band of rDeltaF508 to traffic to the cell surface. Both surface and total expression of rDeltaF508 in NHERF1 knockdown cells were reduced and degradation of surface localized rDeltaF508 was even faster in NHERF1 knockdown cells. Proteasomal and lysosomal inhibitor treatments led to a significant decrease in the accelerated degradation of surface rDeltaF508 in NHERF1 knockdown cells. These results indicate that NHERF1 plays a role in the turnover of CFTR at the cell surface, and that rDeltaF508 CFTR at the cell surface remains highly susceptible to degradation.