Immune and inflammatory alterations in multisystem inflammatory syndrome in children (MIS-C) as compared to Kawasaki disease (KD) were investigated in South Africa, a region of unique genetic background and high infectious disease burden. The observational study included MIS-C and KD patients during 4 severe acute respiratory syndrome coronavirus 2 waves (June 1, 2020-March 31, 2023) plus 12 healthy controls. Clinical features, routine inflammatory markers, hematological parameters, lymphocyte subsets and plasma inflammatory cytokines/chemokines were compared between groups. We enrolled 68 MIS-C, 18 KD, and 12 healthy controls. MIS-C patients had higher rates of Intensive Care Unit admission compared to KD (46% vs 17%; P = .03) and longer hospital stay (8.5 vs 6 days; P < .001). 8 MIS-C but no KD patients had an ejection fraction of < 40% (P = .07). Median lymphocyte counts were decreased in MIS-C, 1.2 cells/μL (interquartile range 0.7-2.3) versus KD 2.5 cells/μL (interquartile range 1.2-3.7), P = .02. Median CD3 + T-cell counts were lower in MIS-C (P = .04). Children with MIS-C had a higher median N-terminal pro-B-type natriuretic peptide of 5836 ng/L (1784-25,698) versus 7 ng/L (88-3262), P < .001 and Troponin T 25 ng/L (9-73) versus 7 ng/L (4-24), P = .01. Majority of cytokines/chemokines were elevated in both MIS-C and KD. When MIS-C was stratified by severity, significant differences in C-reactive protein (P < .001), total lymphocytes (P = .01), and N-terminal pro-B-type natriuretic peptide (P = .01) were observed. Inflammatory cytokine and chemokine levels were markedly raised in both KD and MIS-C. 3 markers were highlighted as indicators of MIS-C severity. There is a strong overlap in inflammatory marker alterations between MIS-C and KD at presentation in the African setting.