The tumorigenic origin and progression capacity of isolated tumor cells in breast cancer sentinel lymph nodes are uncertain. True lymph node metastases are often associated with aberrant protein expression by means of immunohistochemistry. Therefore, evaluation of isolated tumor cells by immunohistochemistry for proteins often overexpressed in breast cancer such as cyclin D1 and p53 could provide relevant information with regard to the malignant potential of these cells. Of 383 consecutive patients with primary invasive breast cancer and sentinel lymph node involvement, 40 had isolated tumor cells in the sentinel lymph nodes, from which 16 sentinel lymph nodes contained isolated tumor cells (n = 16) in newly cut sections that could successfully be immunostained for cyclin D1 and p53. Immunohistochemistry was performed on the primary tumor as well as on the isolated tumor cells in the sentinel lymph nodes. Similarly stained sections of patients with sentinel lymph nodes micro- (n = 15) and macrometastases (n = 15) served as controls. Sentinel lymph node isolated tumor cells as a group showed significantly lower expression of cyclin D1 and p53 compared with micro- and macrometastases. Comparing cyclin D1 expression of the primary tumor with the corresponding sentinel lymph node metastases showed an increased expression in micro- and macrometastases (P = .08 and P = .0025, respectively) compared with the corresponding primary tumor. In patients with sentinel lymph node isolated tumor cells, however, there was no substantial difference in cyclin D1 expression between the primary tumor and the corresponding isolated tumor cells. This supports the hypothesis that some of these cells may be displaced benign cells or concern tumor cells with limited malignant potential compared with micro- and macrometastases.