B cells drive antibody formation and T cell activation. This study aimed to describe the clinical indications, efficacy and adverse events (AEs) for the B-cell depleting agent, rituximab, in a large cohort of children with lupus. Prescribing records and the UK JSLE Cohort Study database identified rituximab use. Sixty-three patients received 104 courses of intravenous rituximab over a 10-year period. Patients were aged 12.2 (IQR 9.0-13.9) years at diagnosis and 50 (79%) were female. They had disease for 1.4 (0.2-3.0) years at the time of rituximab. Lupus nephritis was the most common indication (36% of first courses). Clinical biomarkers, 2.5 (1.6-4.3) months after treatment, demonstrated a statistically significant improvement in ESR, C3, C4, creatinine, albumin, haemoglobin, anti-dsDNA titres and urine albumin:creatinine ratio. IgG, IgA and IgM levels decreased (p < 0.01). Oral corticosteroid dose significantly reduced after rituximab (dose before 0.26 (0.09-0.44) mg/kg, after 0.17 (0.09-0.30) mg/kg; p = 0.01)). AEs occurred in 19 (18%) of all courses including; delayed second dose (8%), Ig replacement (2%) and infusion reactions (6%; anaphylaxis 2%). The global BILAG score showed a trend toward improvement (before 4.5 (2.0-9.0), after 3.0 (2.0-5.0); p = 0.16). Rituximab improves disease activity in children with lupus and serious AEs are infrequent. Controlled studies are required.