Uterine leiomyosarcoma is one of the aggressive malignancies with a poor clinical outcome. Stathmin, a microtubule-destabilizing protein, has been reported to be overexpressed in many malignant tumors including uterine leiomyosarcoma. The activity of stathmin in microtubule destabilization is regulated by the protein phosphorylation. Eribulin is a microtubule-targeting agent which has been approved for treatment of the patients with inoperable or recurrent breast cancer and soft tissue tumors such as uterine leiomyosarcoma. We explored the role of stathmin in the antiproliferative effect of eribulin in leiomyosarcoma cell line (SKN). Eribulin stimulated stathmin phosphorylation and decreased stathmin protein expression in SKN. Although neither inhibitors of protein kinase A nor CaMKII affected the eribulin-induced stathmin phosphorylation, a protein phosphatase 2A (PP2A) activator FTY720 attenuated the phosphorylation. In addition, eribulin reduced the levels of PP2A A and C subunits. Notably, stathmin knockdown decreased the inhibitory effects of eribulin on cell viability, and stathmin overexpression potentiated the efficacy. Stathmin expression was markedly downregulated in eribulin resistant SKN lines we established. These results suggest the significance of stathmin dynamics in antiproliferative activity of eribulin in uterine leiomyosarcoma.