In enzymology, a protein-disulfide reductase (EC 1.8.1.8) is an enzyme that catalyzes the chemical reaction

protein dithiol + NAD(P)+ ${\displaystyle \rightleftharpoons }$ protein disulfide + NAD(P)H + H⁺

The 3 substrates of this enzyme are protein dithiol, NAD⁺, and NADP⁺, whereas its 4 products are protein disulfide, NADH, NADPH, and H⁺.

This enzyme belongs to the family of oxidoreductases, specifically those acting on a sulfur group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is protein-dithiol:NAD(P)+ oxidoreductase. Other names in common use include protein disulphide reductase, insulin-glutathione transhydrogenase, disulfide reductase, and NAD(P)H2:protein-disulfide oxidoreductase.

As of late 2007, 8 structures have been solved for this class of enzymes, with PDB accession codes 1UC7, 1VRS, 1Z5Y, 2FWE, 2FWF, 2FWG, 2FWH, and 2PPT.