Fever with generalised lymphadenopathy is a common presentation in clinical practice. A degree of lymphadenopathy is frequently a characteristic of established systemic lupus erythematosus (SLE), but it is rarely the primary presenting feature. A 25-year-old man presented with night sweats, weight loss and generalised lymphadenopathy. A chest computed tomography scan confirmed the presence of mediastinal, hilar and axillary lymphadenopathy, with bilateral pleural effusions. The double stranded DNA antibody (anti-dsDNA) was absent. Subsequently, there was mild renal impairment and a renal biopsy showed lupus nephritis. Anti-dsDNA was positive using an alternative assay. Treatment with prednisolone and mycophenolate mofetil led to considerable clinical improvement. Extensive lymphadenopathy as the first clinical manifestation of SLE is rare and this case also illustrates the variable results obtained from different anti-dsDNA antibody assays.