BACKGROUND: Reconstruction of major neurosurgical resections can present a significant challenge. We examine our results in relation to major co-morbidities such as preoperative cerebrospinal fluid (CSF) leak, history of smoking, and perioperative radiation therapy. METHODS: From 1997 to 2004, 22 patients requiring neurosurgical or head and neck resection for cancer reconstructed with 24 flaps were retrospectively examined from a single institution. RESULTS: Of the 22 patients, 7 had a CSF leak at the time of surgery. One patient died of a stroke postoperatively. Of the remaining six patients, two had partial flap necrosis (33%). In contrast, of the 15 patients (17 flaps) without CSF leak, 3 had partial flap necrosis (18%, no statistical significance). However, all flaps survived with resolution of their CSF leak. Smokers had a higher rate of partial flap necrosis (30%) versus non-smokers (14%), alhough this was not statistically significant. Only one of the patients that received perioperative radiation (11 of 22 patients) developed partial flap necrosis. CONCLUSIONS: Our data supports the concept that free tissue transfer is a viable option in reconstruction of cranial defects. Difficult problems, such as recurrent CDS leaks and large irradiated wounds, can be successfully managed and resolved using this technique.