Background: The complement pathway is a potential target for the treatment of severe COVID-19. We evaluated the safety and efficacy of ravulizumab, a terminal complement C5 inhibitor, in patients hospitalised with severe COVID-19 requiring invasive or non-invasive mechanical ventilation. Methods: This phase 3, multicentre, open-label, randomised controlled trial (ALXN1210-COV-305) enrolled adult patients (aged ≥18 years) from 31 hospitals in France, Japan, Spain, the UK, and the USA. Eligible patients had a confirmed diagnosis of SARS-CoV-2 that required hospitalisation and either invasive or non-invasive mechanical ventilation, with severe pneumonia, acute lung injury, or acute respiratory distress syndrome confirmed by CT scan or x-ray. We randomly assigned participants (2:1) to receive intravenous ravulizumab plus best supportive care (BSC) or BSC alone using a web-based interactive response system. Randomisation was in permuted blocks of six with stratification by intubation status. Bodyweight-based intravenous doses of ravulizumab were administered on days 1, 5, 10, and 15. The primary efficacy endpoint was survival based on all-cause mortality at day 29 in the intention-to-treat (ITT) population. Safety endpoints were analysed in all randomly assigned patients in the ravulizumab plus BSC group who received at least one dose of ravulizumab, and in all randomly assigned patients in the BSC group. The trial is registered with ClinicalTrials.gov, NCT04369469, and was terminated at interim analysis due to futility. Findings: Between May 10, 2020, and Jan 13, 2021, 202 patients were enrolled in the study and randomly assigned to ravulizumab plus BSC or BSC. 201 patients were included in the ITT population (135 in the ravulizumab plus BSC group and 66 in the BSC group). The ravulizumab plus BSC group comprised 96 (71%) men and 39 (29%) women with a mean age of 63·2 years (SD 13·23); the BSC group comprised 43 (65%) men and 23 (35%) women with a mean age of 63·5 years (12·40). Most patients (113 [84%] of 135 in the ravulizumab plus BSC group and 53 [80%] of 66 in the BSC group) were on invasive mechanical ventilation at baseline. Overall survival estimates based on multiple imputation were 58% for patients receiving ravulizumab plus BSC and 60% for patients receiving BSC (Mantel-Haenszel analysis: risk difference –0·0205; 95% CI –0·1703 to 0·1293; one-sided p=0·61). In the safety population, 113 (89%) of 127 patients in the ravulizumab plus BSC group and 56 (84%) of 67 in the BSC group had a treatment-emergent adverse event. Of these events, infections and infestations (73 [57%] vs 24 [36%] patients) and vascular disorders (39 [31%] vs 12 [18%]) were observed more frequently in the ravulizumab plus BSC group than in the BSC group. Five patients had serious adverse events considered to be related to ravulizumab. These events were bacteraemia, thrombocytopenia, oesophageal haemorrhage, cryptococcal pneumonia, and pyrexia (in one patient each). Interpretation: Addition of ravulizumab to BSC did not improve survival or other secondary outcomes. Safety findings were consistent with the known safety profile of ravulizumab in its approved indications. Despite the lack of efficacy, the study adds value for future research into complement therapeutics in critical illnesses by showing that C5 inhibition can be accomplished in severely ill patients. Funding: Alexion, AstraZeneca Rare Disease.