Purpose: To study patient safety in third molar surgery, where two different doses of S-ketamine were administered for pain relief and compared to a placebo (saline). The primary focus was capillary oxygen saturation of the blood (SpO(2)) and secondarily, alterations in respiratory rate, blood pressure, pulse or adverse events. Methods: One hundred and sixty-eight subjects were included in a randomised, placebo-controlled, double-blind trial. The two subanaesthetic study drugs were low-dose S-ketamine (0.125 mg/kg) and high-dose S-ketamine (0.25 mg/kg). Every patient was sedated with midazolam prior to infusion of the investigational drug. The teeth were surgically removed according to a routine clinical procedure, under local anaesthesia. Results: Primary end-point for the safety aspects was capillary oxygen saturation (SpO(2)) after administration of the investigational drug was finished. A significant difference was found between the placebo and the high-dose group at that point (p = .021), with a decrease of saturation in the high-dose group. The lowest saturation and the number of registrations of SpO(2) <90% did not show any difference between groups. Oxygen supplementation was given in circa 40% of the cases with no differences between the intervention groups. No other significant differences between groups regarding saturation or respiratory rate were noted. Conclusion: In this study, it was safe to use adjunct preoperative single-dose intravenous S-ketamine 0.25 mg/kg body weight for pain relief, in midazolam-sedated patients receiving third molar surgery. There were no serious adverse events or symptoms of overdose nor any clinically relevant effects on circulatory or respiratory parameters.