The semen-derived enhancer of virus infection (SEVI) is natural amyloid material that has been shown to substantially increase viral attachment and infectivity of HIV in cells. We previously reported that synthetic monomeric and oligomeric amyloid-targeting molecules could form protein-resistive coatings on SEVI and inhibit SEVI- and semen-mediated enhancement of HIV infectivity. While oligomeric amyloid-binding compounds showed substantial improvement in apparent binding to SEVI compared to monomeric compounds, we observed only a modest correlation between apparent binding to SEVI and activity for reducing SEVI-mediated HIV infection. Here, we synthesized amyloid-binding polyacrylate-based polymers and polymeric nanoparticles of comparable size to HIV virus particles (~150 nm) to assess the effect of sterics on the inhibition of SEVI-mediated enhancement of HIV infectivity. We show that these polymeric materials exhibit excellent capability to reduce SEVI-mediated enhancement of HIV infection, with the nanoparticles exhibiting the greatest activity (IC50 value of ~4 μg/mL, or 59 nM based on polymer) of any SEVI-neutralizing agent reported to date. The results support that the improved activity of these nanomaterials is likely due to their increased size (diameters = 80-200 nm) compared to amyloid-targeting small molecules, and that steric interactions may play as important a role as binding affinity in inhibiting viral infection mediated by SEVI amyloids. In contrast to the previously reported SEVI neutralizing, amyloid-targeting molecules (which required concentrations at least 100-fold above the Kd to observe activity), the approximate 1:1 ratio of apparent Kd to IC50 for activity of these polymeric materials, suggests the majority of polymer molecules that are bound to SEVI contribute to the inhibition of HIV infectivity enhanced by SEVI. Such size-related effects on physical inhibition of protein-protein interactions may open further opportunities for the use of targeted nanomaterials in disease intervention.