Tau aggregation into insoluble filaments is the defining pathological hallmark of tauopathies. However, it is not known what controls the formation and templated seeding of strain-specific structures associated with individual tauopathies. Here, we use cryo-electron microscopy (cryo-EM) to determine the structures of tau filaments from corticobasal degeneration (CBD) human brain tissue. Cryo-EM and mass spectrometry of tau filaments from CBD reveal that this conformer is heavily decorated with posttranslational modifications (PTMs), enabling us to map PTMs directly onto the structures. By comparing the structures and PTMs of tau filaments from CBD and Alzheimer’s disease, it is found that ubiquitination of tau can mediate inter-protofilament interfaces. We propose a structure-based model in which cross-talk between PTMs influences tau filament structure, contributing to the structural diversity of tauopathy strains. Our approach establishes a framework for further elucidating the relationship between the structures of polymorphic fibrils, including their PTMs, and neurodegenerative disease. Display omitted •Cryo-EM structures of human brain-derived tau filaments from a four-repeat tauopathy•Cryo-EM and MS of tau filaments enable PTM mapping directly onto atomic models•Comparing tauopathies reveals that ubiquitination of tau can mediate fibril diversity•Integrated structural biology elucidates principles of PTM-mediated fibril assembly Structural and mass spectrometry-based proteomics of tau filaments, including their posttranslational modifications, from corticobasal degeneration and Alzheimer’s disease point to how cross-talk between posttranslational modifications influences fibril structure, contributing to the structural diversity of tauopathy strains.