We herein demonstrate an oncogenic role for signal transducer and activator of transcription (STAT)-3alpha (the full length STAT3 isoform), which also mediates autocrine human GH (hGH)-stimulated oncogenicity, in human endometrial carcinoma (EC) cells. Autocrine hGH stimulated Y705 phosphorylation of STAT3 and STAT3-mediated transcriptional activity in a SRC and Janus-2 Kinase dependent manner in human EC cell lines. Forced expression of a constitutively active variant of STAT3alpha increased proliferation, anchorage-independent, three-dimensional (3D) Matrigel, and xenograft growth and promoted epithelial-mesenchymal transition, migration, and invasion of EC cells. Conversely, the oncogenic capacity of EC cells was significantly impaired by treatment with JSI-124, an inhibitor of STAT3 phosphorylation and activity, small interfering RNA-mediated depletion of STAT3alpha, or a dominant-negative variant of STAT3alpha. Furthermore, the enhanced EC cell oncogenicity stimulated by autocrine hGH, was also abrogated by functional inhibition or small interfering RNA-mediated depletion of STAT3alpha. STAT3alpha may therefore be a common mediator of oncogenic signaling pathways stimulating progression of EC.