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OBJECTIVES. The risk of persistent multisystem dysfunction following multisystem inflammatory syndrome in children (MIS-C), a severe postviral complication of COVID-19, remains unknown.METHODS. We investigated long-term outcomes in patients younger than 21 years with MIS-C (n = 173) vs without MIS-C (n = 14 190) up to 4.5 years after COVID-19 in the Montefiore Health System (March 2020 to August 2024). MIS-C status was based on International Classification of Diseases, Tenth Revision codes and Centers for Disease Control and Prevention and World Health Organization criteria. 1:2 propensity score matching and Cox proportional hazards regression with multivariable adjustment were performed.RESULTS. Compared with patients without, patients with MIS-C showed markedly higher risk of cardiovascular disorders (adjusted hazard ratio [aHR] = 13.88 [4.69–41.07], P < .001), hypertension (aHR = 8.86 [4.12–19.06], P < .001), gastrointestinal disorders (aHR = 9.48 [2.66–33.71], P < .001), respiratory disorders (aHR = 3.46 [2.21–5.42], P < .001), and neurological disorders (aHR = 2.02 [1.22–3.34], P = .007). Preexisting hypertension (9.25% of patients with MIS-C vs 6.94% of controls) significantly predicted cardiovascular, neurological, respiratory, and gastrointestinal outcomes. Each 1-year increase in age was associated with increased risk of shock (aHR = 1.06 [1.02–1.11]) and chronic kidney disease (CKD) (aHR = 1.06 [1.01–1.12]). Preexisting diabetes (1.73% of patients with MIS-C) was associated with a 49-fold increased risk of CKD. Kaplan-Meier analysis showed higher persistent risk in the MIS-C group across all outcomes, ranging from 6.8% for CKD to 35.2% for respiratory disorders. Sensitivity analysis using different definitions of MIS-C corroborated our main findings.CONCLUSIONS. MIS-C is associated with broad multisystem morbidity persisting years after acute COVID-19, challenging earlier reports of transient illness. Structured long-term follow-up, including routine blood pressure monitoring, neurological and mental-health screening, and cardiovascular and renal surveillance, with coordinated multidisciplinary care is warranted.