Elevated activin A levels in serum, cyst fluid, and peritoneal fluid of ovarian cancer patients suggest a role for this peptide hormone in disease development. We hypothesize activin A plays a role in ovarian tumor biology, and analyzed activin-mediated pro-oncogenic signaling in vitro, and the expression of activin signaling pathway molecules in vivo. Activin A regulation of Akt and GSK, and the effects of repressing the activities of these molecules (with pharmacological inhibitors) on cellular proliferation were assessed in the cell line, OVCA429. Activin A activated Akt, which phosphorylated GSK, repressing GSK activity in vitro. Activin A stimulated cellular proliferation, and repression of GSK augmented activin-regulated proliferation. To validate in vitro observations, immunostaining of the A subunit of activin A and phospho-GSK/ (Ser9/21) was performed, and the correlation between immunoreactivity levels of these markers and survival, was evaluated in benign serous cystadenoma, borderline tumor, and cystadenocarcinoma microarrays. Analysis of tissue microarrays revealed that A expression in epithelia didn't correlate with survival or malignancy, but expression was elevated in stromal cells from carcinomas when compared to benign tumors. Phospho-GSK/ (Ser9/21) staining was more intense in mitotically active carcinoma cells, and exhibited a polarized localization in benign neoplasms that was absent in carcinomas. Notably, lower phospho-GSK/ (Ser9/21) immunoreactivity correlated with better survival for carcinoma patients (P = 0.046). Our data is consistent with a model in which activin A may mediate ovarian oncogenesis by activating Akt and repressing GSK to stimulate cellular proliferation.