Objective To evaluate tuberculosis pleurisy diagnosis and drug resistance in pleural effusion using Xpert Mycobacterium tuberculosis /Rifampicin (Xpert MTB/RIF) combined with enzyme-linked immunospot assay ELISPOT (T-SPOT.TB). Methods In this study, 101 cases diagnosed with tuberculous pleurisy in Tianjin Haihe Hospital from June 2012 to October 2016 and 79 cases with pleural effusion due to other diseases during the same period were enrolled. Their pleural effusion samples were collected for Xpert MTB/RIF and T-SPOT.TB detection, and BACTEC MG1T960 pleural liquid culture and drug sensitivity related examination were carried out. Using the result of BACTEC MG1T960 pleural liquid culture as a reference standard, the results of Xpert MTB/RIF and T-SPOT.TB were evaluated. Results In the patients with tuberculous pleurisy, the sensitivity of Xpert MTB/RIF and T-SPOT.TB was 82.18% [95% CI (0.78, 0.85)] and 88.12% [95% CI (0.84, 0.91)] respectively with statistical difference (χ2=5.591, P = 0.018) , the specificity was 96.10% [95% CI (0.94, 0.98)] and 98.73% [95% CI (0.97, 0.99)] without significant difference (χ2=1.022, P = 0.312). Using BACTEC MU1T960 pleural liquid culture as the standard, the kappa values of Xpert MTB/RIF and T-SPOT.TB were 0.277 and 0.668 respectively. Comparing Xpert MTB/RIF with BACTEC MU1T960 liquid culture in the diagnosis of Rifampicin resistance rate, the kappa value was 0.786, which represented the two methods were in excellent agreement. Conclusions The sensitivity of T-SPOT.TB diagnosis combined with the specificity of Xpert MTB/RIF not only shorten the time of diagnosis but also improve the accuracy of diagnosis of tuberculous pleurisy and reduce the misdiagnosis rate, therefore they are useful for early diagnosis of tuberculous pleurisy. Furthermore Xpert MTB/RIF helps to make a quick judgement on the resistance to Rifampicin.