Amplified expression of p185HER-2, the protein product of the HER-2/neu proto-oncogene, appears to be involved in carcinogenesis of human mammary epithelial cells. Our data suggest that an extracellular 130 Kda glycoprotein released from breast carcinoma cells may be related to the ectodomain of p185HER-2: (1) Both cellular p185HER-2 and extracellular p130, when reduced and alkylated, reacted with antipeptide antibody against the N-terminus of the HER-2 protein [alpha N(HER-21)] and reactivity was blocked by cognate peptide; (2) Neither p130 nor other extracellular proteins reacted with antiserum against the C-terminus of p185HER-2 [alpha C(HER-2)]; (3) Partial proteolysis of p185HER-2 generated an immunoreactive fragment of 130 kDa that was similar to extracellular p130; (4) Both p130 and p185HER-2 contained carbohydrate that bound to Con-A Sepharose; (5) The amount of p130 released from breast cells corresponded to the levels of expression of cellular p185HER-2. Release of the ectodomain of p185HER-2 from breast carcinoma cells may be involved in their malignant growth and may be a useful marker for assessing the expression of p185HER-2 in human tumors.