BACKGROUND: The clinical manifestations of extrapulmonary tuberculosis (E-TB) vary according to site of disease, so we tested the hypothesis that IFN-γ producing T-cell responses also vary in parallel. Therefore we conducted a prospective, blinded, observational study to evaluate the diagnostic performance of blood T-SPOT.TB according to the various sites of E-TB. METHODS: From April 2008 to August 2010, all patients with suspected E-TB were enrolled at a tertiary hospital in an intermediate TB-burden country. Final diagnosis in patients with suspected E-TB was classified by clinical category. RESULTS: A total of 368 patients with suspected E-TB were enrolled; 196 (53%) were classified as having TB, including 119 (32%) with confirmed TB, 34 (9%) probable TB, and 43 (12%) possible TB; the remaining 172 (47%) were classified as not having TB. After excluding patients with possible TB, the T-SPOT.TB was more sensitive in patients with chronic forms of E-TB such as lymph node or osteoarticular TB (93%, 95% CI 83%-97%) than in patients with acute forms of E-TB such as TB meningitis or miliary TB (79%, 95% CI 66%-87%, P = 0.03). CONCLUSIONS: The diagnostic performance of the blood T-SPOT.TB differs among patients with various clinical manifestations of E-TB.