The use of microvascular free tissue transfer has allowed the reconstruction of increasingly complex defects in higher risk patients after head and neck cancer resections. However, the combination of these factors also gives rise to a higher risk for the development of complications. This study was performed to establish the pretreatment factors associated with complication development after microvascular free tissue transfer for the reconstruction of defects resulting from head and neck cancer ablations, with particular attention to the role of comorbid conditions. A retrospective cohort study was conducted including 200 consecutive microvascular free tissue transfers performed for the reconstruction of surgical defects in the head and neck region at a single tertiary care institution. Comorbidity severity was assessed using the Charlson comorbidity index, a novel approach to comorbid staging in this setting. The flap survival rate was 98 percent. Complications developed in 56 cases (28 percent), with multiple complications occurring in 21 of these cases (10.5 percent). Univariate analysis revealed that prior radiation treatment (p = 0.03), anesthesia time over 10 hours (0.05), and advanced Charlson comorbidity grade (0.002) were associated with an increased risk for the development of complications. However, only the presence of advanced Charlson grade proved significant after multivariate analysis (odds ratio 3.9; 95 percent CI = 1.5 to 10.1). In addition, increasing Charlson grade (p = 0.003) and age over 70 years (p = 0.04) correlated with increasing complication severity. Systemic complications occurred in 28 patients (14 percent), with advanced Charlson grade being the only significant factor associated with the development of complications after controlling for confounding factors (odds ratio 3.8; 95 percent CI = 1.5 to 9.7). In patients over 70 years of age, increasing operative time also impacted on the development of systemic complications (p = 0.002), especially in patients with advanced Charlson grades (0.01). Recipient site complications occurred in 30 patients (15 percent), with history of prior radiation therapy being the only factor associated with increased risk by multivariate analysis (odds ratio 2.5; 95 percent CI = 1.1 to 5.7). No factors predicted the development of donor-site complications, which occurred in 11 cases (5.5 percent). The median hospital stay for the entire population was 16 days. The development of complications increased the median hospital stay by 7.5 days (p < 0.001). The effect of the development of complication on hospital stay remained significant even after controlling for the effects of confounding variables (relative risk = 9.87; 95 percent CI = 5.9 to 19.9). Microvascular surgery is a highly successful and relatively safe method for the reconstruction of large head and neck defects. The Charlson comorbidity index grading may be useful for identifying patients at increased risk for the development of complications after microvascular reconstruction, allowing for improved perioperative planning. In addition, patients with prior radiation exposure have a significantly higher risk for developing complications at the recipient site. Although advanced age is not associated with an increased risk for complications, older patients may be more sensitive to the effects of prolonged anesthesia and are likely to develop more severe complications.