We evaluated the potential of F-18-FDG PET/CT and diffusion-weighted imaging (DWI) to monitor the histologic response in patients with extremity osteosarcoma receiving neoadjuvant chemotherapy, using sequential PET/CT and MR imaging. Methods: We prospectively registered 28 patients with high-grade osteosarcoma treated with 2 cycles of neoadjuvant chemotherapy and surgery. All patients underwent sequential F-18-FDG PET/CT and MR imaging before (PET/MR1) and after neoadjuvant chemotherapy (PET/MR2). Maximum standardized uptake value (SUV), tumor volume based on MR imaging (MRV), and the mean apparent diffusion coefficient (ADC) values were measured on PET/MR1 (SUV1, MRV1, and ADC1) and PET/MR2 (SUV2, MRV2, and ADC2). The percentage changes in maximum SUV (Delta SUV), MRV (Delta MRV), and ADC (Delta ADC) were calculated, and the correlations among these parameters were evaluated. After surgery, the effects of neoadjuvant chemotherapy were graded histopathologically: grades III and IV (necrosis of >= 90%) indicated a good response, and grades I and II (necrosis of < 90%) indicated a poor response. The optimum cutoff values of Delta SUV, Delta MRV, Delta ADC, and their combination for predicting histologic response were assessed by single- and multi-receiver-operating-characteristic curve analysis. Results: Twenty-seven patients were enrolled in the present study after 1 patient with inadequate acquisition of MR imaging was excluded. Delta SUV and Delta ADC negatively correlated with each other (rho = -0.593, P = 0.001), and Delta MRV did not correlate with Delta SUV or Delta ADC. The cutoff value, sensitivity, specificity, and accuracy for predicting good histologic response were <= -52%, 67%, 87%, and 78%, respectively, for Delta SUV and. 13%, 83%, 73%, and 78%, respectively, for Delta ADC. However, Delta MRV did not predict histologic response. Sensitivity, specificity, and accuracy were 83%, 87%, and 85%, respectively, using the combined criterion of Delta SUV <= -31% and Delta ADC > 13%. Conclusion: In the current preliminary study, both PET/CT and DWI are useful for predicting histologic response after neoadjuvant chemotherapy in osteosarcoma. Combining PET/CT and DWI may be an effective method to predict the histologic response of patients to neoadjuvant chemotherapy.