Background: Systemic onset Juvenile Idiopathic Arthritis (SoJIA) is an auto-inflammatory disease that might be complicated by the life-threatening macrophage activation syndrome (MAS). Survivin, antiapoptotic protein, is associated with significant tissue damage and/or poor response to treatment. We sought to investigate its potential role as indicator of disease activity and predictor of MAS in SoJIA. Methods: We conducted a prospective controlled study that comprised 22 physician-diagnosed SoJIA patients and 20 healthy age and sex matched children as a control group. Patients were subjected to clinical and laboratory assessment every 2 months for one year to detect disease relapse or MAS. Serum survivin was measured at enrollment and in case of activity or MAS development. Other inflammatory markers of activity and MAS were also assayed including CRP, ESR, serum ferritin, ferritin/ESR ratio and triglycerides. Results: Over one year of follow up, ten Patients (45.5%) developed both systemic and articular activity with or without MAS, one patient (4.5%) developed systemic activity only, 5 patients (22.7%) had only articular activity and six patients (27.3%) remained in remission. Serum survivin, ferritin, ESR and the ferritin/ESR ratio were high during activity and even higher in the patients who developed MAS. Ferritin/ESR ratio above three had a 100% sensitivity and 83% specificity in the diagnosis of MAS [Area under the curve (AUC) = 0.96]. Serum survivin level above 25 pg/ml had 100% sensitivity and 90% specificity in detection of disease activity [AUC = 0.96] and a serum level above 67 pg/ml had 100% sensitivity and 94.7% specificity in the prediction of MAS [AUC = 0.99]. Conclusion: Survivin might be a potential marker of SoJIA disease activity with special value in the prediction of MAS. Our conclusions are limited by the sample size.