To report on the Confidential Enquiry into Perioperative Equine Fatalities 4 (CEPEF4). Confidential, observational, prospective, multicentre, cohort study. 47,396 horses/ponies undergoing general anaesthesia (GA). Characteristics of each GA (249 variables) were collected. Outcomes after seven days were ALIVE (or discharged), EUTHANASIA or DEAD. Logistic regression analysed patient demographics and the anaesthetic drugs (p < 0.05). Data were collected from 47,396 GAs in 93 centres in 28 countries. Death rates were 1.2% overall, 0.6% for cases classified as NON-COLIC and 4.2% for COLIC. For NON-COLICs (227 deaths from 39,798 NON-COLICs), the main three causes of death were fractures (35.7%), abdominal complications (18.1%) and central nervous system problems (13.2%). Logistic regression analyses revealed an increase in the odds of death for pregnant mares, geriatrics, thin horses, those with a higher American Society of Anesthesiologists grade, urgent procedures and those lasting < 1 hour or > 2 hours. Ketamine infusions and plasma lactate measurement during maintenance were associated with elevated risk. By contrast, monitoring invasive arterial pressure, end-tidal CO2, blood gases and body temperature were each associated with reduced odds of death. Premedication with agonist-antagonist/partial-agonist opioids with non-steroidal anti-inflammatory drugs and administration of α2-adrenoceptor agonists during recovery, alone or with acepromazine, were associated with reduced odds of death. CEPEF4 reports a reduction in the death rate compared with CEPEF2 in 2002: overall 1.2% versus 1.9%, colic death rate 4.2% versus 7.8% and non-colic death rate 0.6% versus 0.9%. Healthy horses still die, the majority because of fractures during recovery. We identified factors that may influence clinical decision-making and enhance patient safety. The CEPEF4 database will continue to provide clinically applicable information, with potential for further insights and improvements in equine anaesthesia.