The Endoplasmic Reticulum (ER) is site of production of secretory and membrane proteins in eukaryotic cells. The ER does not contain catabolic devices and misfolded proteins generated in its lumen must be dislocated across the ER membrane before clearance by cytosolic proteasomes (ER-Associated Degradation, ERAD). How misfolded proteins are dislocated across the ER membrane is a matter of controversy. For example, it remains to be established if polypeptide unfolding is always required. If unfolding is a pre-requisite for dislocation as emerging evidences seem to indicate, it is likely that the incorrect set of disulfide bonds established during unsuccessful folding-attempts that precede selection for ERAD must be reduced to eliminate tertiary and quaternary structures that could hamper dislocation. The lumen of the mammalian ER contains more than 20 members of the PDI family, a handful of which plays a role in ERAD. Here we add the atypical, membrane-bound reductase TMX1 to this list and we show that TMX1 preferentially acts on membrane-tethered folding-defective polypeptides essentially ignoring the same misfolded ectodomains, when not associated to the ER membrane. As such, TMX1 is the first example of a topology-specific client protein redox catalyst acting both in the folding and in the degradative pathways.