Conjugated polymer nanoparticles are being developed for a variety of diagnostic and theranostic applications. The conjugated polymer, F8BT, a polyfluorene derivative, was used as a model system to examine the biological behavior of conjugated polymer nanoparticle formulations stabilized with ionic (sodium dodecyl sulfate; F8BT-SDS; similar to 207 nm; -31 mV) and nonionic (pegylated 12-hydroxystearate; F8BT-PEG; similar to 175 nm; -5 mV) surfactants, and compared with polystyrene nanoparticles of a similar size (PS200; similar to 217 nm; -40 mV). F8BT nanoparticles were as hydrophobic as PS200 (hydrophobic interaction chromatography index value: 0.96) and showed evidence of protein corona formation after incubation with serum-containing medium; however, unlike polystyrene, F8BT nanoparticles did not enrich specific proteins onto the nanoparticle surface. J774A.1 macrophage cells internalized approximately similar to 20% and similar to 60% of the F8BT-SDS and PS200 delivered dose (calculated by the ISDD model) in serum-supplemented and serum-free conditions, respectively, while cell association of F8BT-PEG was minimal (<5% of the delivered dose). F8BT-PEG, however, was more cytotoxic (IC50 4.5 mu g cm(-2)) than F8BT-SDS or PS200. The study results highlight that F8BT surface chemistry influences the composition of the protein corona, while the properties of the conjugated polymer nanoparticle surfactant stabilizer used determine particle internalization and biocompatibility profile.