Background Medical abortion became an alternative method of pregnancy termination following the development of prostaglandins and antiprogesterone in the 1970s and 1980s. Recently, synthesis inhibitors of oestrogen (such as letrozole) have also been used to enhance efficacy. The most widely researched drugs are prostaglandins (such as misoprostol, which has a strong uterotonic effect), mifepristone, mifepristone with prostaglandins, and letrozole with prostaglandins. More evidence is needed to identify the best dosage, regimen, and route of administration to optimise patient outcomes. This is an update of a review last published in 2011. Objectives To compare the effectiveness and side effects of different medical methods for first trimester abortion. Search methods We searched CENTRAL, MEDLINE, Embase, Global Health, and LILACs on 28 February 2021. We also searched Clinicaltrials.gov and the World Health Organization's (WHO) International Clinical Trials Registry Platform, and reference lists of retrieved papers. Selection criteria We considered randomised controlled trials (RCTs) that compared different medical methods for abortion before the 12th week of gestation. The primary outcome is failure to achieve complete abortion. Secondary outcomes are mortality, surgical evacuation, ongoing pregnancy at follow‐up, time until passing of conceptus, blood transfusion, side effects and women's dissatisfaction with the method. Data collection and analysis Two review authors independently selected and evaluated studies for inclusion, and assessed the risk of bias. We processed data using Review Manager 5 software. We assessed the certainty of the evidence using the GRADE approach. Main results We included 99 studies in the review (58 from the original review and 41 new studies). 1. Combined regimen mifepristone/prostaglandin Mifepristone dose: high‐dose (600 mg) compared to low‐dose (200 mg) mifepristone probably has similar effectiveness in achieving complete abortion (RR 1.07, 95% CI 0.87 to 1.33; I2 = 0%; 4 RCTs, 349...