A carbon nanotube (CNT) can be toxic to a living cell by binding to proteins and then impairing their functionalities; however, an efficient screening method that examines the binding capability of a CNT to protein molecules in vitro is still unavailable. Here, we show that a nanopore-based sensor can be used to investigate CNT-protein interactions. With proof-of-principle molecular dynamics simulations, we have measured ionic currents in a nanopore when threading a CNT-protein complex through the pore and demonstrated that the CNT's binding capability, and thus potential nanotoxicity, can be inferred from electric signals. We have then further investigated mechanics and energetics of CNT-protein interactions with the nanopore sensor. These findings indicate that solid-state nanopores have the potential to be ultrasensitive and high-throughput sensors for nanotoxicity. © 2012 American Chemical Society.