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Objective: To assess the appropriateness of expanded serological activity eligibility criteria for belimumab use in the UK systemic lupus erythematosus (SLE) population (and possibly other countries), which includes patients with either anti-double-stranded DNA (anti-dsDNA) positivity or hypocomplementaemia rather than both criteria., Methods: This post-hoc analysis used data from three randomised, double-blind, placebo-controlled phase III belimumab trials: BLISS-52 (BEL110752; NCT00424476), BLISS-76 (BEL110751; NCT00410384) and BLISS-SC (BEL112341; NCT01484496). Patients with SLE were stratified by high disease activity (HDA): HDA1, Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score ≥10, low complement and positive anti-dsDNA; and HDA2, SELENA-SLEDAI ≥10 and either low complement or positive anti-dsDNA., Results: This analysis included 660 HDA1 patients (n=396 on intravenous treatment; n=264 on subcutaneous treatment) and 969 HDA2 patients (n=532 on intravenous treatment; n=437 on subcutaneous treatment). Significant improvements were observed at week 52 with belimumab versus placebo, irrespective of subgroups or drug formulations, in SLE Responder Index (SRI) 4 response (OR (95% CI): HDA1 intravenous 2.7 (1.8 to 4.1); HDA2 intravenous 2.3 (1.61 to 3.26); HDA1 subcutaneous 2.2 (1.22 to 3.85); HDA2 subcutaneous 1.8 (1.17 to 2.74)); proportion of patients achieving ≥4-point reduction in SELENA-SLEDAI score (OR (95% CI): HDA1 intravenous 2.6 (1.7 to 3.9); HDA2 intravenous 2.1 (1.49 to 3.03); HDA1 subcutaneous 2.3 (1.30 to 4.14); HDA2 subcutaneous 1.9 (1.21 to 2.84)); patients with no worsening in Physician Global Assessment (OR (95% CI): HDA1 intravenous 2.0 (1.3 to 3.1); HDA2 intravenous 1.7 (1.17 to 2.45); HDA1 subcutaneous 2.3 (1.18 to 4.40); HDA2 subcutaneous 1.8 (1.11 to 2.92)); and risk of severe flares (HR (95% CI): HDA1 intravenous 0.6 (0.37 to 0.81); HDA2 intravenous 0.6 (0.43 to 0.86); HDA1 subcutaneous 0.52 (0.30 to 0.92); HDA2 subcutaneous 0.59 (0.37 to 0.94))., Conclusion: Broadening the HDA population to include either low complement or positive anti-dsDNA, rather than both, would enable more UK patients to receive SLE treatment and experience improved clinical outcomes., Competing Interests: Competing interests: TM, MI, DB, CW and DR are employees of GSK and hold stocks and shares in the company. IB is a National Institute for Health Research (NIHR) senior investigator and is funded by Versus Arthritis and the NIHR Manchester Biomedical Research Centre. IB has also received speaker’s bureau and advisory board grants from UCB, has participated in advisory boards and steering committees for AstraZeneca, is a member of Independent Data Safety Boards for Medimmune and MS, has received grants from Genzyme Sanofi, and has participated in advisory boards for Eli Lilly. DDC reports participation in advisory boards and consultancies for GSK, Human Genome Sciences, Eli Lilly and Roche, and has received consulting fees and/or has participated in clinical trials for GSK, Bristol-Myers Squibb, TEVA, Merck Serono and Eli Lilly., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)