We found that Trx1-mediated disulfide reduction changes the conformation and functional properties of the CD30 ectodomain. In the reduced state, CD30 lost its ability to interact with its cognate ligand CD30L or agonistic antibodies. The presence of catalytically active Trx1 impeded CD30-dependent signaling in the YT lymphoma cell line, as demonstrated by its effect on CD25 and FasL expression, as well as its influence on cytotoxicity against Fas-expressing target cells.