Tuberculosis prevention treatment (TPT) is crucial to the eradication of tuberculosis (TB). Through a comprehensive review and meta-analysis, we compared the efficacy and safety of different TPT regimens. We searched PubMed, Google Scholar, andmedrxiv.orgwith search terms Tuberculosis Preventive Treatment, TPT, efficacy, safety, and drug regimens for TPT and all RCT, irrespective of age, setting, or co-morbidities, comparing at least one TPT regimen to placebo, no therapy, or other TPT regimens were screened and those reporting either efficacy or safety or both were included. The meta-analysis data were synthesized with Review Manager and the risk ratio (RR) was calculated. Out of 4465 search items, 15 RCTs (randomized-controlled trials) were included. The TB infection rate was 82/6308 patients in the rifamycin plus isoniazid group (HR) as compared to 90/6049 in the isoniazid monotherapy (H) group (RR: 0.89 (95% CI: 0.66, 1.19; p=0.43). A total of 965/6478 vs 1065/6219 adverse drug reactions (ADRs) occurred in HR and H groups respectively (RR: 0.86 (95%CI: 0.80 0.93); P<0.0001). Efficacy analysis of the rifampicin plus pyrazinamide (RZ) vs H showed that the risk ratio of infection rate was not considerably varied (RR: 0.97 (95% CI: 0.47, 2.03); P=0.94). Safety analysis showed in 229/572 patients developed ADRs in rifampicin plus pyrazinamide as compared to 129/600 ADRs in the isoniazid group. (RR: 1.87 (95% CI: 1.44, 2.43)). Safety analysis of only rifamycin (R) vs H group showed 23/718 ADRs in R vs 57/718 ADRs in H group (RR: 0.40 (95% CI: 0.25 0.65); P=0.0002). Rifamycin plus isoniazid (3HP/R) has no edge over other regimens in terms of efficacy but this regimen was found significantly safer as compared to any other regimens used for TPT. Rifampicin plus pyrazinamide (RZ) was found equally efficacious but less safe as compared to other regimens.