Expression of protein tyrosine phosphatase PTP4A2 (also known as PRL2) has been examined in a variety of human carcinomas, although its role in breast cancer remains inconclusive. Since the majority of previous breast cancer studies utilized tissue biopsies composed of heterogeneous cell populations, we hypothesized that an examination of PTP4A2 expression in carcinoma cells isolated by laser capture microdissection (LCM) would provide a more accurate means of assessing its predictive value. From investigations of 247 human breast cancer biopsies collected under standardized, stringent conditions, total RNA was extracted from LCM-procured carcinoma cells to perform microarray analyses to identify gene signatures associated with breast cancer behavior. Expression of PTP4A2 was corroborated by real-time quantitative polymerase chain reaction (qPCR) and referenced to estrogen and progesterone receptor levels. Patient outcomes for overall and disease-free survival were more favorable (p = 0.004 and p = 0.001, respectively) when the expression of PTP4A2 in breast carcinomas was increased compared to patients with biopsies with decreased PTP4A2 levels. PTP4A2 expression determined either by microarray or qPCR was elevated in either estrogen receptor (ER)-positive or progestin receptor (PR)-positive breast cancer biopsies compared to ER-negative or PR-negative biopsies. However, PTP4A2 expression was only correlated with overall survival in PR-positive breast carcinomas. These data suggest that PTP4A2 mRNA expression alone may serve as a biomarker for prediction of a breast cancer patient's risk of recurrence and overall survival.