The skull base is an anatomically challenging location that is unique in that it requires three-dimensional considerations when formulating a reconstruction plan. Various methods have been described for repair including open, endoscopic and endoscopic-assisted approaches. Each of these can have complications that can arise either directly from access to the lesion or defect, or indirectly arising from patient characteristics, anesthetic considerations, as well as postoperative care. It is of utmost importance for the surgeon to select the appropriate technique and surgical access depending on the location of the lesion as well as the patient's specific anatomic variations. In this chapter, we highlight morbidity and mortality arising from various anatomical locations encountered during access for repair of skull base defects as well as those that may arise from lumbar drain placement. We also highlight some treatment protocols from the literature that will aid in the management of these complications. Careful patient selection, review of preoperative imaging, and meticulous technique are of utmost importance to prevent life-threatening problems. Surgeons should have intimate knowledge regarding management as well as methods in place to minimize their occurrence.