Study DesignRetrospective study. ObjectivesTo analyze predictors of major blood loss (MBL) during multilevel arthrodesis for adult spinal deformity (ASD). Summary of Background DataASD surgery is associated with substantial blood loss. MethodsWe identified 237 patients with ASD who underwent spinal arthrodesis of five or more levels by one surgeon and who had complete data on blood loss. MBL was defined as normalized blood loss above the 75th percentile (ie, >49%). Patients with MBL were compared with those without MBL with respect to baseline characteristics, preoperative laboratory values, and surgical factors. Alpha level = 0.05. ResultsA total of 176 patients (74%) had MBL. On univariate analysis, the MBL and non-MBL groups differed with respect to diagnosis of osteoporosis (p = .002), curve type (p = .012), number of levels fused (p < .001), and presence/type of osteotomy (p < .001). The groups were similar in age (p = .605) and proportion of patients undergoing revision surgery (p = .410). Multivariate analysis identified the following predictors of MBL: three-column osteotomy (odds ratio [OR] = 4.1, 95% confidence interval [CI] = 1.7, 9.7), arthrodesis of 11 or more levels (OR = 3.2, 95% CI = 1.4, 7.6), malalignment in both coronal and sagittal planes (OR = 3.2, 95% CI = 1.4, 7.3), and osteoporosis (OR = 2.4, 95% CI = 1.1, 5.4). ConclusionPatients with ASD undergoing spinal arthrodesis of five or more levels are at risk for MBL. Three-column osteotomy, arthrodesis of ≥11 levels, malalignment in both coronal and sagittal planes, and osteoporosis appear to be risk factors for MBL. Level of EvidenceLevel III.