Hypofibrinogenaemia is associated with excessive bleeding after cardiac surgery. Our aim was to compare the efficacy and safety of weight-adjusted vs empiric dosing of fibrinogen replacement in cardiac surgery. In the Fibrinogen Replenishment in Cardiac Surgery (FIBRES) RCT, patients (n=735) received fibrinogen concentrate (4 g) or cryoprecipitate (10 units). In this post-hoc analysis, patients were grouped into quartiles based on increasing weight-adjusted dosing. Generalised estimating equations were used to account for hospital site, age, sex, surgical complexity, urgency, and critical preoperative status. The primary outcome was the number of units of red blood cells transfused within 24 h of cardiopulmonary bypass. Secondary outcomes included allogeneic blood components within 24 h, tamponade or major bleeding, and thromboembolic complications, ischaemic complications, or both within 28 days of cardiopulmonary bypass. The median weight-adjusted doses were 52 mg kg−1 of fibrinogen concentrate (inter-quartile range IQR, 45–61; n=372) and 1.30 units per 10 kg of cryoprecipitate (IQR, 1.11–1.54; n=363). When patients were divided into quartiles of lowest to highest weight-adjusted dosing, no differences were seen in the primary outcome of red blood cell units transfused within 24 h of cardiopulmonary bypass between the lowest and highest quartiles in either the fibrinogen group (adjusted relative risk RR=0.90; 95% confidence interval CI, 0.71–1.13; P=0.36) or the cryoprecipitate group (adjusted RR=1.04; 95% CI, 0.76–1.43; P=0.80). Results were similar for all secondary outcomes. Outcomes for the lowest and highest weight-adjusted doses of fibrinogen replacement were comparable. Weight-adjusted dosing does not appear to offer advantages over empiric dosing in this context. NCT03037424.