A randomized, controlled trial evaluated four experimental therapies for Ebola virus disease (EVD) in the Democratic Republic of Congo (DRC) during an outbreak that began in August 2018. Patients with a positive Ebola virus RNA result from a reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay were enrolled and randomly assigned to receive either ZMapp (a triple monoclonal antibody), remdesivir (an antiviral), MAb114 (a single monoclonal antibody), or REGN-EB3 (a triple monoclonal antibody). The primary endpoint was death at 28 days. At 28 days, 35.1% of patients in the MAb114 group and 33.5% in the REGN-EB3 group died, compared to 49.7% and 51.3% in the ZMapp group, respectively. These results indicate that both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality. Factors such as shorter symptom duration before admission and lower baseline viral load and serum creatinine and aminotransferase levels correlated with improved survival. Four serious adverse events were judged potentially related to the trial drugs. The trial demonstrated that scientifically and ethically sound clinical research can be conducted during disease outbreaks and can inform outbreak response. The study highlights the importance of early diagnosis and treatment, as well as the impact of baseline viral load and renal function on mortality. The safety profiles of the four therapies were generally consistent with previous data, though some adverse events were potentially related to the trial drugs. The trial faced challenges including regional violence, mistrust of government and the Ebola response, and logistical difficulties. Despite these challenges, the trial was successfully conducted with the cooperation of national and international health agencies, government leaders, and organizations. The results support the use of MAb114 and REGN-EB3 as effective treatments for EVD, with potential benefits attributed to their single-dose administration compared to multiple infusions of ZMapp and remdesivir. The study underscores the importance of rigorous clinical research in outbreak settings and the need for further exploration of more effective interventions.A randomized, controlled trial evaluated four experimental therapies for Ebola virus disease (EVD) in the Democratic Republic of Congo (DRC) during an outbreak that began in August 2018. Patients with a positive Ebola virus RNA result from a reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay were enrolled and randomly assigned to receive either ZMapp (a triple monoclonal antibody), remdesivir (an antiviral), MAb114 (a single monoclonal antibody), or REGN-EB3 (a triple monoclonal antibody). The primary endpoint was death at 28 days. At 28 days, 35.1% of patients in the MAb114 group and 33.5% in the REGN-EB3 group died, compared to 49.7% and 51.3% in the ZMapp group, respectively. These results indicate that both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality. Factors such as shorter symptom duration before admission and lower baseline viral load and serum creatinine and aminotransferase levels correlated with improved survival. Four serious adverse events were judged potentially related to the trial drugs. The trial demonstrated that scientifically and ethically sound clinical research can be conducted during disease outbreaks and can inform outbreak response. The study highlights the importance of early diagnosis and treatment, as well as the impact of baseline viral load and renal function on mortality. The safety profiles of the four therapies were generally consistent with previous data, though some adverse events were potentially related to the trial drugs. The trial faced challenges including regional violence, mistrust of government and the Ebola response, and logistical difficulties. Despite these challenges, the trial was successfully conducted with the cooperation of national and international health agencies, government leaders, and organizations. The results support the use of MAb114 and REGN-EB3 as effective treatments for EVD, with potential benefits attributed to their single-dose administration compared to multiple infusions of ZMapp and remdesivir. The study underscores the importance of rigorous clinical research in outbreak settings and the need for further exploration of more effective interventions.