Although low-molecular weight protein tyrosines phosphatase (LMW-PTP) has been associated with tumorigenesis and tumor progression, its role is controversial. In this study, we show that alterations in the RhoA activation status caused by knocking-down separately the two main isoforms of LMW-PTP, fast and slow, interfere with the migratory potential of breast cancer cells. Our results highlight the differential role of LMW-PTP isoforms in cancer biology.