We evaluated the low affinity neurotrophin receptor (p75 NTR ) as a marker of breast myoepithelial cells. Immunohistochemical staining for p75 NTR was performed on paraffin sections of 122 malignant breast lesions, 28 benign lesions and the adjacent normal breast tissue. The staining pattern was compared to those of myosin heavy chain and p63. p75 NTR immunostain was consistently positive and compatible with p63 and myosin immunoreactivity in the myoepithelial cells of the normal mammary gland, benign breast lesions (six usual ductal hyperplasias, six specimens with sclerosing adenosis, eight intraductal papillomas, six fibroadenomas), and carcinoma in situ (18 ductal carcinomas in situ, two noninvasive papillary carcinomas, two lobular carcinomas in situ). The luminal cells were negative for p75 NTR , but rare positive cells were noticed in the solid areas of some of the usual ductal hyperplasias. Four of 64 invasive ductal carcinomas (6%) and all metaplastic carcinomas (n ¼ 3, 100%) showed a variable degree of p75 NTR positivity. No p75 NTR expression was found in the malignant cells in all in situ carcinomas, invasive lobular carcinomas (n ¼ 11), tubular carcinomas (n ¼ 10), invasive papillary carcinomas (n ¼ 6), mucinous carcinomas (n ¼ 4), and medullary carcinomas (n ¼ 2). No myosin imunoreactivity was seen in the luminal/tumor cells, but p63 pattern of staining in the luminal/tumor cells was quite similar to that of p75 NTR . Although significant p75 NTR immunoreactivity was noticed in the vessels, nerves, and stromal component of fibroadenomas, no difficulties in the evaluation of the immunostain of myoepithelial cells were encountered. Our study shows that p75 NTR is a useful marker for breast myoepithelial cells and can be used to rule out invasive disease as well as to evaluate difficult for diagnosis sclerosing lesions. Our data suggest a role of neurotrophins in the development of fibroepithelial breast tumors and some of the breast carcinomas. Modern Pathology (2005) 18, 1535-1541.