Patients undergoing microvascular reconstruction are often anemic from a combination of iatrogenic hemodilution and acute blood losses. No major clinical study describes the impact of preoperative anemia on free flap morbidity. The plastic surgery service at a high-volume academic center performed 156 free flaps among 147 patients from December 2005 to December 2010. One hundred thirty-two had a preoperative hemoglobin (Hb) or hematocrit (Hct), with mean values of 11.8±2.4 g/dL and 35.2%±7.0%, respectively. The overall failure rate was 9% (12/132), primarily from vascular thrombosis (6/12). Through logistic regression analysis, Hb and Hct were significant predictors of flap failure (P<0.005) and vascular thrombosis (P<0.05). Fisher exact test revealed a significant increase in failure risk at Hct level less than 30% (Hb<10 g/dL) (relative risk, 4.76, P=0.006), and probit analysis demonstrated an exposure-response relationship to decreased Hct level (P<0.005). These findings support that preoperative anemia could significantly impact free flap morbidity.