The endoplasmic reticulum (ER) contains a highly effective protein quality control system eliminating malfolded proteins by a mechanism called ER-associated protein degradation (ERAD). Here, we unravel the topology of Der1p, a previously identified component of the ERAD system. Der1p contains four transmembrane domains, its N- and C-terminus protrude into the cytoplasm and contribute to its function. Additionally, we describe a yeast homologue of Der1p, Dfm1p, which does not seem to be involved in ERAD. In contrast, a Caenorhabditis elegans orthologue of Der1p, R151.6, is capable of complementing der1-defective phenotypes in yeast.