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Transglutaminases catalyze the covalent cross-linking of substrate proteins to form insoluble protein complexes that are resistant to degradation. Our previous studies demonstrated that transglutaminase-induced cross-linking of tau proteins occurs in Alzheimer disease and progressive supranuclear palsy (PSP). The current study was designed to measure transglutaminase enzyme activity and the mRNA and protein levels of 3 transglutaminase isoforms that are expressed in human brain. Overall, transglutaminase activity was significantly increased in the globus pallidus (182% of control) and pons in PSP (171% of control) but not the occipital cortex (a region spared from pathology). Using a Spearman rank correlation test, we found that tissues with more transglutaminase-activity had more neurofibrillary tangles. Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.