In clinical practice, using different opioid analgesics is common during the induction and maintenance of general anesthesia and for postoperative analgesia. However, if the opioid analgesic could be limited to a single drug, we hypothesized that the risk of adverse drug interactions could be reduced, with fewer adverse effects. We examined the use of oxycodone as a single opioid in a well-defined cohort of orthopedic patients undergoing general anesthesia. In this retrolective, monocentric investigation, we reviewed data from 83 patients who underwent general anesthesia and received intravenous oxycodone as the sole analgesic (0.075 mg/kg during induction and 0.05 mg/kg during maintenance). The use of oxycodone during general anesthesia and the postoperative pain scores were recorded. Safety was evaluated by the measurement of hemodynamic changes (blood pressure, heart rate), the detection of pathologic changes in the electrocardiogram, changes of the peripheral oxygen saturation, and by the assessment of adverse effects. There was no significant change in peripheral oxygen saturation or the electrocardiogram during or while recovering from general anesthesia. Heart rate changed only slightly from reversal to recovery (73.3/min versus 78.3/min, p < 0.05) and from prior intubation to recovery (72.5/min versus 78.3/min, p < 0.05). Systolic and diastolic blood pressure did not change significantly from the time points "after intubation" to "after incision," and "during recovery." Fifty-nine percent (n = 49) of patients' records revealed pain scores with a maximum of 3 on a numeric rating scale (NRS) of 0 to10 during the postoperative period. In 45 percent of patients (n = 37), further analgesics such as acetaminophen, dipyrone, or additional doses of oxycodone were used. No severe adverse events were recorded. According to data from 93 percent of patients (n = 77), nausea scores were less than 3 on a NRS of 0 to 10. Oxycodone can be used as the sole opioid in orthopedic surgery with good intra- and postoperative efficacy and safety; ie, without clinically relevant changes in hemodynamic and respiratory parameters.