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Objectives Current first-line treatment of SLE is antimalarials, conventional immunosuppressants (cIS) and glucocorticoids (GC) with biologics usually reserved for refractory disease. However, GC exposure, damage accrual and mortality are highest within the first year of SLE. Predictors of severe SLE and early use of biologics are also predictors of good response to rituximab. Deferring biologic use may therefore be inefficient and miss the opportunity to prevent severe disease. FIRST will evaluate the clinical and cost-effectiveness of adding rituximab to cIS and GC at the onset of moderate-to-severe SLE compared with placeboMethods FIRST is a multicentre, double-blind, randomised, placebo-controlled study in the UK. Key inclusion criteria are age >=5 years; within 12 months of SLE diagnosis; within 4 weeks of starting a first cIS at screening; and moderate-to-severe activity based on Easy-BILAG. 128 participants will be randomised 1:1 to rituximab or placebo, in addition to standard therapy such as cIS, hydroxychloroquine and GC. Infusions will be given on days 1 and 15 at months 0 and 6, each preceded by intravenous methylprednisolone in both arms. Outcome measures include LLDAS, DORIS, Easy-BILAG, cumulative GC dose, EQ-5D, SF-36, resource use and adverse events over 12 monthsResults The primary objective is to assess whether greater cumulative time in LLDAS over 12 months is achieved in the rituximab group compared with placebo. We will also evaluate secondary outcomes including cumulative time in DORIS remission, BILAG flares, GC exposure, SLICC damage index, HRQoL, healthcare costs and safetyConclusions FIRST will be the first trial of its kind to incorporate: (1) a biologic as first-line immunosuppressive in early SLE; (2) a time-on-target instead of response endpoint, capturing improvement, flare prevention, new organ involvement, GC exposure and cIS changes in a single outcome; (3) a whole life course population (4) a pragmatic design allowing changes in GC and cIS. We hypothesise that FIRST will include a broader spectrum of SLE presentations and first-line rituximab will reduce long-term damage accrual, cumulative GC exposure and the need for rescue therapies. Early optimisation of SLE management and effective disease control may also lead to greater patient satisfaction and improved quality of life outcomes.