IntroductionBelimumab, an anti-B-lymphocyte-stimulator antibody, is approved for the treatment of active, autoantibody-positive systemic lupus erythematosus (SLE). Rituximab, a B cell-depleting anti-CD20 antibody, remains in the SLE treatment armamentarium despite failed trials in lupus nephritis and extrarenal lupus. These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE. This study aims to evaluate and compare the efficacy, safety and tolerability of subcutaneous (SC) belimumab and a single cycle of rituximab in patients with SLE with belimumab alone.Methods and analysisBLISS-BELIEVE is a three-arm, randomised, double-blind, placebo-controlled, 104-week superiority study. Two hundred adults with SLE will be randomised 1:2:1 to arm A, belimumab SC 200 mg/week for 52 weeks plus placebo at weeks 4 and 6; arm B, belimumab SC 200 mg/week for 52 weeks plus rituximab 1000 mg at weeks 4 and 6; arm C, belimumab SC 200 mg/week plus standard of care for 104 weeks. The 52-week treatment period (arms A and B) is followed by a 52-week observational phase. The primary efficacy endpoint is the proportion of patients with disease control (SLE Disease Activity Index (SLEDAI)−2K≤2, without immunosuppressants and with a prednisone-equivalent dose of ≤5 mg/day) at week 52. Major secondary efficacy endpoints are the proportion of patients in clinical remission (defined as SLEDAI-2K=0, without immunosuppressants and corticosteroids) at week 64, and the proportion of patients with disease control at week 104. Safety endpoints include the incidence of adverse events (AEs), serious AEs and AEs of special interest.Ethics and disseminationWithin 6 months of the study’s primary manuscript publication, anonymised individual participant data and study documents can be requested for further research fromwww.clinicalstudydatarequest.com.Trial registration numberNCT03312907; Pre-results.