Objective The purpose of this study is to assess the ability of apparent diffusion coefficient (ADC) values in differentiating Ewing sarcoma and osteosarcoma. Materials and methods This retrospective cross-sectional observational study included a total of 35 patients with a recent diagnosis of Ewing sarcoma (n = 13) and osteosarcoma (n = 22) who underwent conventional MRI and diffusion-weighted imaging (DWI). Three ADC measurements from the areas of the lowest diffusivity in ADC maps (ADC(min)), and other areas with low diffusivity (ADC(other)), were made independently by two observers on pre-treatment MRI, and the means of these measurements were compared using independent samples t-test. Intraclass correlation coefficient was calculated for inter-observer agreement. Results There was a significant difference between the ADC(min) (P < 0.001) and ADC(other) (P < 0.001) in Ewing sarcoma and osteosarcoma for both observers. For Ewing sarcoma and osteosarcoma, mean ADC(min) was 0.566 +/- 0.07 and 1.193 +/- 0.33 x 10(-3) mm(2)/s; 0.551 +/- 0.08 and 1.182 +/- 0.33 x 10(-3) mm(2)/s; and mean ADC(other) was 0.813 +/- 0.11 and 1.510 +/- 0.35 x 10(-3) mm(2)/s; 0811 +/- 0.12 and 1.501 +/- 0.33 x 10(-3) mm(2)/s for observers 1 and 2, respectively. Inter-observer correlation coefficient for mean ADC(min) was 0.994 and for mean ADC(other) was 0.995. Conclusion Diffusion-weighted imaging and ADC values could be used in the differentiation of Ewing sarcoma and osteosarcoma in borderline cases.