Postsurgical infection risk is correlated with subcutaneous tissue oxygenation. Mild hypercapnia augments cutaneous perfusion. We tested the hypothesis that peripheral tissue oxygenation increases as a function of arterial PCO2 in surgical patients. Twenty patients were randomly assigned to intra-operative end tidal PCO2 of 3.99 (control) or 5.99 kPa (hypercapnia). All other anaesthetic management was per protocol. Tissue oxygen partial pressure, transcutaneous oxygen tension, cerebral oxygen saturation, and cardiac output were measured. Mean (SD) subcutaneous tissue oxygen tension was 8.39 (1.86) kPa in control and 11.84 (2.53) kPa hypercapnia patients (p = 0.014). Cerebral oxygen saturation was 55 (4)% for control vs. 68 (9)% for hypercapnia (p = 0.004). Neither cardiac index nor transcutaneous tissue oxygen tension differed significantly between the groups. Mild intra-operative hypercapnia increased subcutaneous and cerebral oxygenation. Increases in subcutaneous tissue oxygen partial pressure similar to those observed in patients assigned to hypercapnia are associated with substantial reductions in wound infection risk.