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Glioblastoma (GBM) is a deadly and common primary brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity. Sex differences may play a role in patient outcome. Previous studies showed that ER-α36, a variant of the estrogen receptor (ER), mediated non-genomic estrogen signaling and is highly expressed in many ER-negative malignant tumors. ER-α36 also associates with epidermal growth factor receptor (EGFR). The primary purpose of this study is to investigate the cross talk between ER-α36 and EGFR in estrogen-mediated GBM cell proliferation. Here, we showed that ER-α36 was highly expressed and confirmed that ER-α36 co-labels with EGFR in human GBM samples using immunohistochemical techniques. We also investigated the mechanisms of estrogen-induced proliferation in ER-α-negative cell lines. We found that GBM cells showed varying responsive to mitogenic estrogen signaling which correlated with ER-α36 expression, and knockdown of ER-α36 diminished the response. Exposure to estrogen also caused upregulation of cyclin protein expression in vitro. We also found that low concentration of estrogen promoted SRC-Y-416 and inhibited SRC-Y-527 phosphorylation, corresponding with activated SRC signaling. Inhibiting SRC or EGFR abolished estrogen-induced mitogenic signaling, including cyclin expression and MAPK phosphorylation. Cumulatively, our results demonstrate that ER-α36 promotes non-genomic estrogen signaling via the EGFR/SRC/MAPK pathway in GBM. This may be important for the treatment of ER-α-negative GBMs that retain high level of ER-α36, since estrogen may be a viable therapeutic target for these patients., (© 2022 International Federation for Cell Biology.)