Objective: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA). Early diagnosis is critical. Classification criteria for MAS in sJIA perform less well in the setting of cytokine-directed therapies. The goal herein was to explore a simple ratio of serum ferritin to the erythrocyte sedimentation rate (ESR) for diagnosis of MAS in the setting of sJIA, and to assess ferritin alone as a screening tool for identifying MAS of multiple etiologies. Methods: Data from a large international cohort of sJIA patients with and without MAS, and from hospitalized patients with systemic infection (SI), were assessed for the ferritin:ESR ratio and ferritin alone to identify MAS among sJIA patients. Moreover, data from a smaller cohort of MAS patients associated with multiple etiologies and febrile hospitalized controls were explored. For both cohorts and controls, receiver operating characteristic curves (ROCs) for the ferritin:ESR ratio and ferritin alone were constructed, and areas under the curves (AUCs) were calculated. The Youden index was used to determine the optimal ferritin:ESR ratio and ferritin alone cut points for diagnosis. Results: A ferritin:ESR ratio of 21.5 was 82% sensitive and 78% specific for diagnosing sJIA-MAS versus active sJIA without MAS. Ferritin alone with a set sensitivity of 95% (screening tool) had an 89.3% specificity of identifying all-cause MAS versus febrile hospitalized children. Conclusion: The ferritin:ESR ratio is a practical tool for diagnosing MAS among sJIA patients, and serum ferritin alone is a remarkable screening tool for identifying MAS among febrile hospitalized children.