Abstract Anion exchanger 2 (AE2) is a member of the anion exchanger gene family, which includes three additional members, AE1, AE3, and AE4. They are also known as Na+-independent Cl-/HCO3- exchangers, and their major function is to regulate intracellular pH and chloride concentration. All four isoforms have several N-terminally truncated variants that are often expressed cell type specifically. Red blood cells express the full-length AE1 isoform that interacts with ankyrin, an adapter protein linking plasma membrane to the spectrin-based membrane skeleton. This membrane skeleton association is essential for maintaining the membrane integrity of red blood cells. AE3 variants are mainly found in the brain and heart, whereas AE4 is localized in the kidney. Anion exchanger 2 is expressed in every cell line and tissue studied thus far, and it has been mainly localized to the plasma membrane. However, we found two types of localization/targeting of the AE2 protein in several of the cell lines studied. The protein was localized to either the plasma membrane or the Golgi complex, depending on the cell type. The AE2 variant expressed in these cells was identified as the full-length AE2 protein. The determinants of differential intracellular targeting were assessed. We hypothesized that Golgi-AE2 is anchored to the Golgi membranes via its association with the Golgi membrane skeleton. We were able to show that the Golgi localization of AE2 correlated with the cell type specific expression of Ank195, a Golgi membrane skeletal protein. In cells where AE2 was targeted to the plasma membrane, Ank195 was not expressed. In addition, the detergent insolubility and co-redistribution properties of AE2 and Ank195 strongly suggested that these proteins interact with each other. The Golgi membrane skeleton has been shown to be necessary for maintaining the Golgi structure. Our studies were consistent with these findings, showing that in cells in which AE2 expression was reduced by using AE2-specific antisense oligonucleotides, the Golgi complex was dispersed. The spectrin-based membrane skeleton was probably partially detached from the Golgi membranes leading to breakdown of the Golgi structure and disorganization of the microtubules associated with it. The present findings suggest that the targeting of AE2 is cell type specific, and that Golgi-localized AE2 serves as a membrane association site for the spectrin-based Golgi membrane skeleton, thereby participating in the maintenance of the Golgi structure.