This paper describes the isolation and partial purification of the straight fibrils that occur in the neurons of Pick's disease. Pick fibrils are highly insoluble in a variety of solvents. These fibrils were shown to be sodium dodecyl sulfate insoluble even in the presence of a reducing agent at elevated temperatures. This allowed the selective isolation of the fibrils using the SDS boiling procedure and sucrose gradient centrifugation that have been described for isolation of paired helical filaments of Alzheimer's disease. The isolated fibrils retained the native morphology seen in tissue sections, but some appeared to become unraveled to yield a paired helical appearance. These results indicate that the Pick fibrils have many chemical and structural characteristics in common with Alzheimer paired helical filaments, and suggest that these two diseases may be closely related.