Serum GP73 levels are significantly increased in patients with hepatocellular carcinoma (HCC), potentially providing a marker for early detection. However, GP73 is an integral membrane protein localized to the cis Golgi and is not known to be secreted. Based on its presence in sera, we sought to determine whether GP73 might normally be released from cells and to elucidate the mechanism of this release. Indeed, a soluble form of GP73 was released from cultured cells and compared with the Golgi-localized full-length protein, the molecular weight was slightly reduced, suggesting that cleavage releases the GP73 ectodomain. Sequence analysis revealed a proprotein convertase (PC) consensus site, and, indeed, the ubiquitous PC furin was capable of cleaving purified GP73. Further, alanine substitutions in the PC site blocked both the in vitro and the in vivo cleavage of GP73. Using a cleavage-specific antibody, cleaved GP73 was found in the trans Golgi network and endosomes, suggesting that GP73 cleavage occurs as GP73 cycles distal to the early Golgi. We conclude that the endosomal trafficking of GP73 allows for PC-mediated cleavage, resulting in GP73 secretion, and provides a molecular mechanism for its presence as a serum biomarker for HCC.