Extracellular chaperones such as clusterin may contribute to extracellular protein homeostasis in neurodegenerative disorders. It has been implicated in fibrillogenesis and extracellular misfolded protein clearance in Alzheimer disease. We investigated the localization and potential functions of clusterin in familial amyloidotic polyneuropathy (FAP), a neurodegenerative disorder characterized by extracellular deposition of mutant transthyretin (TTR) in the peripheral nervous system. We observed increased clusterin expression in human FAP nerves, in the dorsal root ganglia of mutant TTR transgenic mice with TTR deposition, and in human neuroblastoma cells incubated with oligomeric TTR. Clusterin colocalized with extracellular TTR aggregates in human FAP nerves and was detected in aggregates extracted from FAP tissues. Abolition of clusterin expression using small interfering RNA in a HEK293 cell line that secretes wild-type TTR resulted in increased TTR aggregation in the medium, thus suggesting a protective role for clusterin in inhibition of TTR aggregation. However, under the conditions examined, toxicity of oligomeric TTR in neuroblastoma cells was unaltered by clusterin gene silencing. These data suggest that clusterin can influence TTR aggregation but may not modulate TTR aggregate toxicity or play a role in TTR clearance in FAP. Further studies will elucidate neuroprotective mechanisms conferred by clusterin in FAP and other neurodegenerative diseases.