Objective To systematically review the safety of rifapentine vs. rifampicin for pulmonary tuberculosis. Methods PubMed, EMbase, The Cochrane Library, CBM, VIP, WanFang Data and CNKI databases were electronically searched to collect randomized controlled trials (RCTs) of rifapentine vs. rifampicin for pulmonary tuberculosis up to September 2017. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, meta-analysis was performed by using RevMan 5.3 software. Results A total of 26 RCTs involving 3 624 cases were included. The results of meta-analysis showed that the rifapentine group was superior to the rifampicin group on the incidence of abnormal liver function (RR=0.31, 95%CI 0.32 to 0.47, P<0.000 01), skin rash occurrence rate (RR=0.24, 95%CI 0.16 to 0.37,P<0.000 01), the incidence of leukopenia (RR=0.41, 95%CI 0.31 to 0.54,P<0.000 01), and the incidence of gastrointestinal reaction (RR=0.46, 95%CI 0.37 to 0.57,P<0.000 01) with statistical significance. Conclusions Current evidence shows that compared with rifampicin, rifapentine can effectively reduce the adverse reactions of patients. Due to limited quality and quantity of the included studies, more high quality studies are needed to verify the above conclusion.