Abstract： Objective To investigate the changes of rifampin concentrations in pleural effusion before and after combination treatment with oral and pleural administration of rifampicin by electro-phonophoresis(EP). Methods A self-control study was performed in 32 cases of tuberculous pleurisy treated in the Second Department of Respiratory Medicine of Affiliated Hospital of Zunyi Medical College between September 2016 and January 2018. Based on the weight of each patient, an oral administration of isoniazid (0.3-0.4 g/d), rifampicin (0.45-0.60 g/d),ethambutol(0.75 g/d),and pyrazinamide (1.0-1.5 g/d) were given. After a 5-day traditional anti-tuberculosis treatment, an additional EP treatment was applied by penetrating chest wall to deliver 3 ml of rifampicin. The concentration of rifampicin in 5 ml pleural effusion was measured at 0, 0.5, 1, 2, 4 and 8h after applying EP treatment using high performance liquid chromatography. The measurement data were analyzed by using statistic software SPSS 20.0. The results were expressed by xˉ± s and t test was conducted, with a statistical significance of P<0.05. Results The average concentration of rifampicin in pleural effusion was (2.2 ± 1.1) μg/ml by oral rifampicin alone. The concentration of rifampicin was (2.7±1.1)μg/ml, (3.0±1.4)μg/ml, (3.2±1.2)μg/ml, (2.8±1.2)μg/ml and (1.3± 1.1)μg/ml, respectively, at 0.5 h, 1, 2, 4, 8 h after combining local EP treatment. The results indicated that combining local EP treatment significantly increased the drug concentration in pleural effusion, which lasted for about 5 hours. Conclusions By applying rifampicin into pleural cavity through EP treatment with penetration of the chest wall, the concentration of rifampicin in pleural effusion of patients with tuberculous&nbsp;pleurisy could be increased. Combined with oral administration of rifampicin, this treatment could prolong the effective drug concentration in pleural effusion, which was beneficial to the bactericidal effects of rifampicin.