Pediatric coronavirus disease 2019 (COVID-19) after SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with multisystem inflammatory syndrome in children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared with pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2–infected pediatric patients (pediatric COVID-19) and patients with MIS-C. Patients with MIS-C had patterns of T cell–biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike–specific antibodies at admission. A distinct feature of patients with MIS-C was robust activation of vascular patrolling CX3CR1⁺ CD8⁺ T cells that correlated with the use of vasoactive medication. Last, whereas pediatric COVID-19 patients with acute respiratory distress syndrome had sustained immune activation, patients with MIS-C displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non–MIS-C versus MIS-C SARS-CoV-2–associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8⁺ T cells in the clinical presentation and trajectory of MIS-C.