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Mercury is a potent neurotoxin that can delay neurological development in neonates, and has been proposed to be an environmental risk factor for several neurodegenerative conditions. The mechanisms by which environmental factors may influence the propagation of neurodegenerative diseases are not yet well delineated. However, it is known that neurons require trophic factor support for maintenance and survival following traumatic physical and toxic insults. We found that divalent mercury (HgCl(2)) inhibited ciliary neurotrophic factor and interferon-gamma receptor-mediated Janus tyrosine kinase (Jak)/signal transducers and activators of transcription (STAT) pathway activation in SK-N-BE(2)-C neuroblastoma cell cultures, but did not inhibit the fibroblast growth factor receptor tyrosine kinase. Results of dichlorofluorescein experiments showed increased levels of oxidative stress in HgCl(2)-treated cells that was similar in magnitude to that caused by treatment with H(2)O(2). The antioxidant agents glutathione, N-acetylcysteine, and sodium ascorbate each protected neurons against HgCl(2)-induced inhibition of STAT activation. HgCl(2) also inhibited Jak-STAT signaling in cultures of chick retina neurons, but did not affect signaling in nonneuronal HepG2 cells and chick skeletal myotubes. The specific inhibition of growth factor-mediated Jak-STAT signaling pathways in neurons by HgCl(2)-induced oxidative stress offers a new mechanism by which mercury may produce neurotoxic symptoms in the developing nervous system, promote neurodegeneration in mature neurons, and inhibit recovery following neurotrauma.