To assess the effectiveness of whole-body MRI (WB-MRI) in early diagnosis of chronic recurrent multifocal osteomyelitis (CRMO) and the prediction of clinical response through quantitative MRI features. 20 children (mean age, 10.3 years; range, 5-14 years) with CRMO underwent WB-MRI and were assessed with a clinical score (Jansson) at baseline (median time after first encounter, 8 months) and follow-up (median time after baseline, 11.5 months). Baseline WB-MRI scans were classified as early (within 6 months after first encounter) and late. Clinical responders and non-responders were compared regarding number and localization of bone lesions, lesion volume and T2 signal intensity (SI) ratio (lesion to muscle). Diagnosis of CRMO was made promptly in the early WB-MRI group ( = 10; median, 3 months) compared to the late WB-MRI group ( = 10; 18 months; = 0.006). Bone lesions were mainly located in the lower extremities ( = 119/223; 53%). No significant difference was detected regarding the number of bone lesions and lesion volume in the subgroups of clinical responders ( = 10) and non-responders ( = 10). Responders showed a higher volume reduction of bone lesions at follow-up compared to non-responders ( = 0.03). Baseline and follow-up SI ratios were lower in responders (5.6 and 5.8 6.1 and 7.2; = 0.047 and = 0.005). The use of WB-MRI within 6 months of disease suspicion may serve as a benchmark to support early diagnosis of CRMO. T2 SI ratios and the reduction of lesions' volume correlate with clinical outcome. WB-MRI at an early stage of suspected CRMO plays a key role for early diagnosis. This is the first study showing that quantitative MRI features are suitable for response assessment and can be used as prognostic markers for the prediction of clinical response.