Background: Use of recombinant human bone morphogenetic protein-2 (rhBMP-2) has increased considerably since its introduction in 2002. The complications associated with high-dose rhBMP-2 (≥40 mg) are unknown. The purpose of our study was to determine outcomes and medical and surgical complications associated with high-dose rhBMP-2 at shortterm and long-term follow-up evaluations. Methods: Five hundred and two consecutive adult patients who had received high-dose rhBMP-2 as a part of spinal surgery from 2002 to 2009 at one institution were enrolled. Data were entered prospectively and studied and analyzed retrospectively. Surgical procedures in the thoracic and lumbar spine were included. Major and minor complications were documented intraoperatively, perioperatively, and at the latest follow-up examination. Complications potentially associated with rhBMP-2 use were evaluated for correlation with rhBMP-2 dose. Scoliosis Research Society (SRS) and Oswestry Disability Index (ODI) outcome measures were obtained before and after surgery. Results: On average, 115 mg (range, 40 to 351 mg) of rhBMP-2 was used. The average age of the patients (410 women and ninety-two men) at the time of the index procedure was 52.4 years (range, eighteen to eighty years). There were 265 primary and 237 revision procedures, and 261 patients had interbody fusion. An average of 11.5 vertebrae were instrumented. The average duration of follow-up was forty-two months (range, fourteen to ninety-two months). The diagnoses included idiopathic scoliosis (41%), degenerative scoliosis (31%), fixed sagittal imbalance (18%), and other diagnoses (10%). The rate of intraoperative complications was 8.2%. The rate of perioperative major surgical complications was 11.6%. The rate of perioperative major medical complications was 11.6%. Minor medical complications occurred in 18.9% of the cases, and minor surgical complications occurred in 2.6%. Logistic regression analysis and Pearson correlation did not identify a significant correlation between rhBMP-2 dosage and radiculopathy (r = 20.006), seroma (r = 20.003), or cancer (r =20.05). Significant improvements in the ODI score (from amean of 41 points to amean of 26 points; p < 0.001) and the SRS total score (from amean of 3.0 points to amean of 3.7 points; p < 0.001) were noted at the latest follow-up evaluation. Conclusions: This is the largest study of which we are aware that examines complications associated with high-dose rhBMP-2. Major surgical complications occurred in 11.6% of patients, and 11.6% experienced major medical complications. There was a cancer prevalence of 3.4%, but no correlation between increasing rhBMP-2 dosage and cancer, radiculopathy (seen in 1% of the patients), or seroma (seen in 0.6%) was found. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.