The widespread introduction of enhanced recovery (ER) programmes for surgical patients is driven by the need to improve their outcomes. One of the principles of ER is to use specific perioperative measures that modify the surgical stress response. However, the impact of a complete enhanced recovery programme (ERP) on the stress response has never been examined in a randomised controlled trial (RCT). The primary hypothesis of this study was that, after open liver resection, an ERP alters the stress response compared with standard perioperative care. Ninety-­one patients (45 control; 46 ERP) were enrolled in an RCT. The concentration of stress response markers were analysed in perioperative blood samples, i.e.: IL-­6, IL-­1β, IL-­4, IL-­8, IL-­10, GM-­CSF, IFN-­γ, TNF-α, VEGF, CRP, cortisol, insulin and glucose. Samples were also analysed in 24 patients per group for immunological response markers; i.e. white cell, lymphocyte, CD3, CD4, CD8, CD16, CD19, CD56, HLA-­DR cell counts. Patients randomised to the treatment group received a comprehensive ERP: pre-­admission counselling, preoperative nutritional supplements, preoperative oral carbohydrate loading, goal-­directed fluid therapy, early postoperative feeding and mobilisation. The control group received standard perioperative care. Postoperative morbidity data were collected for all patients and complications graded for severity. ERP and control data sets were compared by ANOVA and appropriate parametric or non-­parametric tests, categorical values were tested with chi-­squared tests In the treatment group, there were more patients with colorectal metastases, who had received preoperative chemotherapy and a higher P-­POSSUM operative severity score, otherwise groups were well-­matched. There was no significant difference in IL-­6, IL-­1β, IL-­4, IL-­8, IL-­10, GM-­CSF, IFN-­γ, TNF-­α, VEGF or CRP responses between groups. Peak serum cortisol was significantly reduced and serum insulin was significantly higher in the treatment group. The incidence and severity of medical complications were significantly less in the treatment group. CD3 counts were significantly lower, but CD19 counts were significantly higher in the treatment group. The study aimed to measure the stress response following liver resection using an ERP compared with standard care and to demonstrate a physiological basis for any clinical outcomes. The significant reduction of postoperative morbidity with an ERP correlated with, and may result from, significant alterations of cortisol and insulin responses, but not cytokine levels, including IL-­6.