P16 expression predicts necrotic response among patients with osteosarcoma receiving neoadjuvant chemotherapy. Although pathologic response to neoadjuvant chemotherapy is highly correlated with survival among patients with osteosarcoma, there are currently no established molecular markers to predict response to chemotherapy. The objective of this study was to investigate the relationship of P16 expression in pretreatment osteosarcoma tumors to pathologic necrotic response after neoadjuvant chemotherapy. A tissue microarray was created from paraffin-embedded pretreatment biopsy specimens of 40 patients with osteosarcoma. Immunohistochemistry was performed with commercially available P16 monoclonal mouse antibody. Expression of P16 was defined as nuclear staining in 30% or greater of cells. Percent tumor necrosis was measured in postchemotherapy resection specimens per established protocols, and 90% or greater tumor necrosis was considered \good.\ Data were abstracted on age, sex, tumor site, and histologic subtype. Univariate and multivariate analyses were performed. The median age was 15 years, 52% were female, and 35% of tumors were located in the femur. P16 expression was present in 62%. Median posttreatment tumor necrosis was 90%, and 55% of patients experienced \good\ chemotherapy response (≥90% necrosis). On univariate analysis, P16 expression correlated positively with median percent necrosis and \good\ chemotherapy response (P=.004 and .003, respectively). On logistic regression analysis, P16 expression was independently associated with chemotherapy response after controlling for age, subtype, sex, and location (odds ratio, 43.5 95% confidence interval, 2.64-708.9 P=.008). In summary, immunohistochemical expression of P16 significantly correlates with chemotherapy response in osteosarcoma. P16 expression may be a useful biomarker to guide treatment selection.Copyright © 2012 Elsevier Inc. All rights reserved.