To demonstrate the effectiveness of microvascular free tissue transfer in reconstructing complex skull base defects. Retrospective chart review. A retrospective chart review was conducted identifying patients with anterior or lateral skull base defects, or both, who underwent microvascular free flap reconstruction. Appropriate demographic, pathological, and preoperative and postoperative clinical data were collected and analyzed. Thirty-five patients with skull base defects were identified, including 8 women (Mean age, 43.9 y; age range, 28-75 y) and 27 men (mean age, 57.9 y; age range, 19-85 y). Defects were secondary to trauma in two cases, whereas the remaining 33 cases were secondary to ablative procedures for a variety of malignant tumors, of which squamous cell carcinoma was the most common (n = 18). The average defect surface area was 89.3 cm(2), and 36 free flaps were used. The most commonly used flap was the rectus myocutaneous (n = 20); however, six different flap types were employed, including three radial forearm fascial flaps. In all, there were seven flap-related complications and there was one total flap loss. A total of 43 postoperative complications occurred in 23 patients, with the most common complications being grouped as intracranial (n = 10), orbital (n = 9), and cardiac (n = 9). The perioperative mortality rate was 5.7%, and the average hospital stay was 13.5 days (range, 7-37 d). The use of microvascular free tissue transfer for reconstruction of complex skull base defects has proven highly successful in the large series presented in the current study. The versatility and reliability of free flaps for such reconstruction are discussed, and helpful hints are given to minimize the complication rate.