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Although pharmacological control of HIV infection is now possible, HIV\u2010associated neurocognitive disorders (HAND) remain intractable. Here, we report that chronic treatment with erythropoietin (EPO) and insulin\u2010like growth factor\u2010I (IGF\u2010I) protects against HIV\/gp120\u2010mediated neuronal damage in culture and in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Initially, we tested the neuroprotective effects of various concentrations of EPO, IGF\u2010I, or EPO+IGF\u2010I from gp120\u2010induced damage in vitro. To assess the chronic effects of EPO+IGF\u2010I administration in vivo, we treated HIV\/gp120\u2010transgenic or wild\u2010type mice transnasally once a week for 4 months and subsequently conducted immunohistochemical analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Low concentrations of EPO+IGF\u2010I provided neuroprotection from gp120 in vitro in a synergistic fashion. In vivo, EPO+IGF\u2010I treatment prevented gp120\u2010mediated neuronal loss, but did not alter microgliosis or astrocytosis. Strikingly, in the brains of both humans with HAND and gp120\u2010transgenic mice, we found evidence for hyperphosphorylated tau protein (paired helical filament\u2010I tau), which has been associated with neuronal damage and loss. In the mouse brain following transnasal treatment with EPO+IGF\u2010I, in addition to neuroprotection we observed increased phosphorylation\/activation of Akt (protein kinase B) and increased phosphorylation\/inhibition of glycogen synthase kinase (GSK)\u20103\u03b2, dramatically decreasing downstream hyperphosphorylation of tau. These results indicate that the peptides affected their cognate signaling pathways within the brain parenchyma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings suggest that chronic combination therapy with EPO+IGF\u2010I provides neuroprotection in a mouse model of HAND, in part, through cooperative activation of phosphatidylinositol 3\u2010kinase\/Akt\/GSK\u20103\u03b2 signaling. This combination peptide therapy should therefore be tested in humans with HAND. 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