BACKGROUND: Recently, there has been an unexplained increase in the incidence of blackwater fever (BWF) in Eastern Uganda. In this study, we evaluated the association between immune complexes, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and the occurrence and recurrence of BWF in children with severe malaria (SM). METHODS: Between 2014 and 2017, children aged 6 months to <4 years hospitalized with SM and community children (CC) were recruited at 2 hospitals in Central and Eastern Uganda. We measured serum circulating immune complexes (cIC) and their relationship to SM complications and postdischarge outcomes, and evaluated effect mediation through G6PD deficiency. RESULTS: In total, 557 children with SM and 101 CC were enrolled. The mean age was 2.1 years. Children with SM had higher cIC levels than CC (P < .001). After controlling for age, sex, and site, cIC were associated with severe anemia, jaundice, and BWF: adjusted odds ratio (aOR), 7.33 (95% confidence interval [CI], 3.45-15.58), P < .0001; aOR, 4.31 (95% CI, 1.68-11.08), P = .002; and aOR, 5.21 (95% CI, 2.06-13.18), P < .0001, respectively. cIC predicted readmissions for SM, severe anemia, and BWF: adjusted incidence rate ratios (aIRR), 2.11 (95% CI, 1.33-3.34), P = .001; aIRR, 8.62 (95% CI, 2.80-26.59), P < .0001; and aIRR, 7.66 (95% CI, 2.62-22.45), P < .0001, respectively. The relationship was most evident in boys where the frequency of the G6PD African allele (A-) was 16.8%. G6PD deficiency was associated with increases in cIC in boys (P = .01) and mediation analysis suggested G6PD deficiency contributes to recurrent severe anemia and BWF via increased cIC. CONCLUSIONS: Immune complexes are associated with hemolytic complications and predict recurrences in SM survivors.