OBJECTIVES: Early and appropriate nutritional support is recommended for critically ill patients. Evidence is conflicting regarding the optimum route of delivery and robust cost-effectiveness evidence is lacking. The objective of the study was to evaluate the cost-effectiveness of early nutritional support via the parenteral (PN) versus the enteral (EN) route in critically ill adults. METHODS: We undertook a cost-effectiveness analysis (CEA) using data from a large, pragmatic, multi-centre RCT that recruited patients from 33 English adult, general critical care units. Resource use and outcome data on 2388 trial patients were used to report cost-effectiveness at 90-days and at one year, and to project lifetime cost-effectiveness. The CEA used information on Health-related Quality of Life (QoL) at 90-days and at one year combined with information on vital status to report Quality-Adjusted Life Years (QALYs). Each QALY was valued using the NICE recommended threshold of willingness-to-pay (£20,000 per QALY) in conjunction with the costs of each route to report the incremental net monetary benefits (INB) of nutritional support via PN versus EN.  RESULTS: Mean QoL at 90-days and one year was similar between the randomised groups. At one year, the PN group had higher costs (£1,580 [95% CI -£792 to £3,951]), similar QALYs (0.013 [95% CI -0.014 to 0.040]) and negative INB (-£1,320 [95% CI -£3,709 to £1,069]) compared to the EN group. When a lifetime time horizon is taken, the INB of PN was positive but with considerable uncertainty surrounding the result (£440 [95% CI -£3,586 to £4,466]). The probabilities that PN is more cost effective were 14% (1 year) and 58% (lifetime), respectively.  CONCLUSIONS: For critically ill adult patients, providing nutritional support via PN versus EN is unlikely to be cost-effective. However, it should be recognised that considerable uncertainty surrounds the cost-effectiveness results, especially when projected over the patient’s lifetime.