We studied T-bet expression in 91 cases of peripheral T-cell lymphoma (PTCL) by immunostaining and found expression in 42 cases (46%), including all 5 lymphoepithelioid lymphoma cases and 12 (86%) of 14 angioimmunoblastic lymphoma cases, but only 9 (25%) of 36 anaplastic large cell lymphoma cases. Expression of T-bet in PTCL correlates with expression of other markers of Th1 T-cell differentiation, including CXCR3 (P < .0001), CD69 (P = .0013), LEF-1 (P = .0007), and OX40/CD134 (P = .005), and absence of expression of markers of Th2 T-cell differentiation, including CD30 (P = .0001) and CXCR4 (P = .0144). Of 22 cases of PTCL immunoreactive for all Th1-associated markers previously studied and nonreactive for Th2-associated markers, 20 (91%) were immunoreactive for T-bet. Of 22 PTCL cases immunoreactive for Th2-associated markers studied and nonreactive for all Th1-associated markers studied, 4 (18%) were immunoreactive for T-bet. The remaining 47 PTCL cases (52%) exhibited incomplete or mixed staining for Th1- and Th2-associated markers, with 18 (38%) of 47 immunoreactive for T-bet. T-bet is a new marker that may contribute to the diagnosis and subtyping of PTCLs. T-bet expression in these neoplasms provides further support for a model of PTCL in which tumor subsets express markers of, and may be derived from, Th1- or Th2-committed T cells.