Large craniofacial defects after tumor ablation are usually reconstructed with the vertical or transverse rectus abdominis myocutaneous flap, which provides reliable coverage. However, such flaps may suffer from significant atrophy and subsequent contour deformity in long-term. The added donor site morbidity, especially in patients with minimal pulmonary reserve, may increase post-operative complications, delay post-operative recovery and prolong hospital stay. The anterolateral thigh (ALT) flap has been extensively used for head and neck reconstruction by the author at The University of Texas M.D. Anderson Cancer Center. Between August 2001 and April 2003, 21 patients with large craniofacial defects were reconstructed with free tissue transfer. The rectus abdominis myocutaneous flap was used in five patients (Group I). The remaining 16 patients (Group II) were reconstructed with the following flaps: ALT flap in 13 patients, lateral arm flap in two patients, and split latissimus dorsi flap in one patient. Facial nerve reconstruction was simultaneously performed in six patients. Mean age in Group I was 67 years and in Group II, 64 years. Mean area of defect requiring resurfacing was 97 cm2 and 106 cm2 in Groups I and II, respectively (P=0.77). Post-operative radiotherapy was given in 15 patients. Post-operative complications included flap congestion in two patients and wound infection in one patient in Group II; hematoma in one patient and ARDS requiring prolonged hospital stay (48 days) in one patient in Group I. Average length of hospital stay was 9.5 days in Group I excluding the one with ARDS, and 5.7 days in Group II. Mean follow-up was 324 days and 253 days for Groups I and II, respectively. All patients are alive to date except one patient who died from stroke 21 months after surgery. The ALT flap seemed to retain bulk well in long-term. All the rectus abdominis myocutaneous flaps suffered significant volume loss with subsequent contour deformity. In conclusion, free flap reconstruction for large craniofacial defects is a safe and reliable procedure. Reconstruction with an ALT flap seems to shorten post-operative recovery and hospital stay most likely due to its minimal donor site morbidity. The ALT flap may also suffer less volume loss. Due to the involvement of neurosurgical procedures, simultaneous harvesting of the rectus abdominis flap is usually not possible. However, the ALT flap can be easily raised simultaneously with tumor ablation, therefore, decreasing overall anesthesia time.