Selenoprotein S (SelS or VIMP) is an intrinsically disordered membrane enzyme that provides protection against reactive oxidative species. SelS is a member of the endoplasmic reticulum-associated protein degradation pathway, but its precise enzymatic function is unknown. Because it contains the rare amino acid selenocysteine, it belongs to the family of selenoproteins, which are typically oxidoreductases. Its exact enzymatic function is key to understanding how the cell regulates the response to oxidative stress and thus influences human health and aging. To identify its enzymatic function, we have isolated the selenocysteine-containing enzyme by relying on the aggregation of forms that do not have this reactive residue. That allows us to establish that SelS is primarily a thioredoxin-dependent reductase. It is capable of reducing hydrogen peroxide but is not an efficient or broad-spectrum peroxidase. Only the selenocysteine-containing enzyme is active. In addition, the reduction potential of SelS was determined to be -234 mV using electrospray ionization mass spectrometry. This value is consistent with SelS being a partner of thioredoxin. On the basis of this information, SelS can directly combat reactive oxygen species but is also likely to participate in a signaling pathway, via a yet unidentified substrate.