The potential neuroprotective capacity of four different sulfated glycans: -derived sulfated galactan (BoSG) (MW > 100 kDa), -derived sulfated fucan (LvSF) (MW90 kDa), high-molecular weight dextran sulfate (DxS) (MW 100 kDa), and unfractionated heparin (UFH) (MW15 kDa), was assessed in response to the HIV-1 proteins, R5-tropic glycoprotein 120 (gp120) and/or trans-activator of transcription (Tat), using primary murine neurons co-cultured with mixed glia. Compared to control-treated cells in which HIV-1 proteins alone or combined were neurotoxic, BoSG was, among the four tested sulfated glycans, the only one capable of showing significant concentration-dependent neuroprotection against Tat and/or gp120, alone or combined. Surface plasmon resonance-based data indicate that BoSG can bind both HIV-1 proteins at nM concentrations with preference for Tat (7.5 × 10 M) over gp120 (3.2 × 10 M) as compared to UFH, which bound gp120 (8.7 × 10 M) over Tat (5.7 × 10 M). Overall, these data support the notion that sulfated glycan extracted from the red alga , BoSG, can exert neuroprotection against HIV-1 Tat and gp120, potentially via direct molecular interactions.