Although combined antiretroviral therapy has significantly improved the prognosis of HIV-1 infected patients and decreased the incidence of HIV-1 associated dementia, the cumulative prevalence of this disease, in particular, mild or asymptomatic neurocognitive impairment, has not decreased. Thus, in addition to active antiretroviral therapy, the search for an effective neuroprotective approach is very important. Sigma-1 receptors are widely distributed in the central nervous system. Sigma-1 receptor agonists are robustly neuroprotective in many neuropathy and neurotoxicity in vivo and in vitro studies. This study aims to investigate possible neuroprotective effects of sigma-1 receptor agonist, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) against HIV-1 protein gp120. Primary cortical neuronal cultures were exposed to gp120 in different concentrations; to investigate neuroprotective effects of sigma-1 receptor agonist, cells were pre-treated with PPBP (10μM) in the presence or absence of pre-incubated sigma-1 receptor antagonist rimcazole (5μM). Cell apoptosis was confirmed with calcein/PI uptake test, lactate dehydrogenase (LDH) leakage assay or TUNEL assay and neurite degeneration was evaluated with morphometry via MAP-2 stained immunofluorescence. The mRNA and protein levels of apoptosis associated bax and bcl-2 were determined with real-time qPCR and Western blot. The results showed that gp120 could induce neuronal apoptosis and neurite degeneration in a concentration dependent manner and PPBP could attenuate the neurotoxicity of gp120. Simultaneously, gp120 could induce low expression of bcl-2 and bax, but only low expression of bcl-2 could be reversed by PPBP. The present data suggest that PPBP, at least, in part protects the neuron against gp120 by regulating bcl-2 expression.