BACKGROUND: Reconstruction of major neurosurgical resections can present a significant challenge because of the morbidity of radiation therapy, cerebrospinal fluid leaks, bacterial contamination from sinus exposure, and functional and cosmetic deformity from the size and location of the defect. The authors present their experience with free tissue reconstruction of scalp and calvarial defects. In particular, the authors examine their results in relation to major comorbidities, such as preoperative cerebrospinal fluid leak, history of smoking, and perioperative radiation therapy. METHODS: From 1997 to 2004, 22 patients requiring neurosurgical or head and neck resection for cancer from a single institution who underwent reconstruction with 24 flaps were examined retrospectively. Factors examined included patient demographics, indication for surgery, type of flap used, exposed critical structures, comorbidity, complications, and outcomes. RESULTS: Of the 22 patients, seven had a cerebrospinal fluid leak present at the time of their reconstructive surgery. Of the seven, one patient died as a result of a stroke postoperatively. Of the remaining six patients, two had partial flap necrosis (33 percent). However, all six flaps survived, with resolution of cerebrospinal fluid leak. In comparison, of the 15 patients (17 flaps) without a cerebrospinal fluid leak, three had partial flap necrosis (18 percent; not significant). With regard to smoking status, the partial flap necrosis rate was 30 percent in smokers versus a rate of 14 percent in nonsmokers, although this was not statistically significant. Only one patient who received perioperative radiation (11 of 22 patients) developed partial flap necrosis. CONCLUSIONS: The authors' data support the concept that free tissue transfer is a viable option in reconstruction of cranial defects. Although complications can occur in this high-risk population, successful reconstruction with free flaps was possible. Difficult problems, such as recurrent cerebrospinal fluid leaks and large irradiated wounds, can be managed and resolved successfully using this technique.