Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic anticancer drugs. Clinically, there are no effective medicines to prevent CIPN, and duloxetine is the only recommended drug to treat the developed CIPN. We have demonstrated the involvement of high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) protein, in the pathogenesis of CIPN. Our clinical and reverse translational research evidence clearly shows that estrogen decline after menopause or ovariectomy promotes the severity of CIPN following paclitaxel treatment, which involves macrophage-derived HMGB1. Paclitaxel directly stimulates HMGB1 release from macrophages, an effect blocked by estrogen via activation of nuclear and membrane estrogen receptors. Ovariectomy also aggravates CIPN following oxaliplatin treatment, which involves HMGB1 derived from non-macrophage cells. Ovariectomized mice exhibit nociceptive hypersensitivity in response to intraplantar injection of HMGB1, which is prevented by repeated treatment with elcatonin, known to restore the ovariectomy-induced downregulation of 5-HT_1A receptors in the spinal cord. We thus suggest that postmenopausal estrogen decline aggravates CIPN possibly through the impairment of estrogen modulation of HMGB1 release and the downstream signals.