Radical penectomy (RP) is infrequently performed as it is reserved for specific cases of penile cancer, hence the paucity of reports regarding surgical and anesthetic considerations. Acute postoperative pain, chronic post-surgical pain, concomitant mood disorders as well as a profound impact on the patient’s quality of life have been documented. This case is of a patient with diabetes and coronary heart disease, who presented with advanced, overinfected penile cancer, depressive disorder and a history of pain of neuropathic characteristics. The patient underwent radical penectomy using a combined spinal-epidural technique for anesthesia. Preoperatively, the patient was treated with pregabalin and magnesium sulphate, and later received a blood transfusion due to intraoperative blood loss. Adequate intra and postoperative analgesia was achieved with L-bupivacaine given through a peridural catheter during one week. Recovery was good, pain was stabilized to preoperative levels and the patient received pharmacological support and follow-up by psychiatry and the pain team.