•SLE occurs in 22% of children with ANA-associated AIC.•Children of age >10 years and ANA titer >1/160 must be monitored long-term, for progression to SLE. Display omitted Autoimmune cytopenia (AIC) in children may be associated with positive antinuclear antibodies (ANA) and may progress to systemic lupus erythematosus (SLE). We evaluated the risk of progression to SLE of childhood-onset ANA-associated AIC. In the French national prospective OBS’CEREVANCE cohort, the long-term outcome of children with ANA-associated AIC (ANA titer ≥1/160) and a subgroup of children who developed SLE were described. ANA were positive in 355 of 1803 (20%) children with AIC. With a median follow-up of 5.8 (range, 0.1-29.6) years, 79 of 355 (22%) patients developed SLE at a median age of 14.5 (1.1-21.4) years; 20% of chronic immune thrombocytopenic purpura, 19% of autoimmune hemolytic anemia, and 45% of Evans syndrome. None of the patients with ANA-negative test developed SLE. Severe manifestations of SLE were observed in 21 patients, and 2 patients died. In multivariate analysis including patients with positive ANA within the first 3 months after AIC diagnosis, age >10 years at AIC diagnosis (relative risk RR, 3.67; 95% confidence interval CI, 1.18-11.4; P = .024) and ANA titer >1/160 (RR, 5.28; 95% CI, 1.20-23.17; P = .027) were associated with the occurrence of SLE after AIC diagnosis. ANA-associated AIC is a risk factor for progression to SLE, especially in children with an initial ANA titer >1/160 and an age >10 years at AIC diagnosis. ANA screening should be recommended in children with AIC, and patients with ANA should be monitored long-term for SLE, with special attention to the transition period. This trial was registered at www.ClinicalTrials.gov as #NCT05937828. A minority of patients presenting as children with chronic autoimmune cytopenia (AIC), manifesting as immune thrombocytopenic purpura or autoimmune hemolytic anemia, will subsequently develop systemic lupus erythematosus (SLE), but which ones? In a prospective cohort study, Granel and colleagues identified a 22% incidence rate of SLE after diagnosis of AIC if the antinuclear antibody (ANA) was ever positive, with the highest risk in children diagnosed after 10 years of age and where the ANA titer exceeded 160. The authors’ work identified a subgroup of patients needing long-term monitoring for later emergence of SLE.