OBJECTIVES: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune inflammatory disease, associated with significant health and socioeconomic burden. Current treatment of SLE involves glucocorticoids, antimalarials, non-steroid anti-inflammatory drugs, and immunosuppressive agents. Belimumab, a human IgG monoclonal antibody specific for soluble human B lymphocyte stimulator protein, is a novel pharmaceutical treatment approved as an add-on therapy in adult SLE patients with highly active disease (autoantibody-positive and low complement levels) despite treatment. The study objective was to estimate the incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) of adding belimumab to the Standard-of-Care (SoC)  treatment of SLE patients with high disease activity in the Greek healthcare setting. METHODS: The analysis is based on the local adaptation of a micro-simulation model. The model follows individual patients over a lifelong period. Data on short-term outcomes were sourced from two randomized controlled trials (BLISS 72/7614). Long-term outcomes were estimated via natural history models developed on the basis of data from the John Hopkins cohort of SLE patients. Direct costs consisted of short-term disease activity related costs, organ damage costs, SoC treatment and belimumab administration costs. Short-term costs and costs of treatment were calculated on the basis of resource utilisation elicited from a panel of experts and using list prices (2013 prices). Organ damage costs were identified through a literature review. Results were discounted at 3.5% for both costs and effects. The study was performed from the perspective of the healthcare payer. RESULTS: Treatment with belimumab+SoC resulted in 0.81 added life years and 0.377 QALYs (Quality-Adjusted Life Years). This resulted in 18,350€ / LYG (Life-Year-Gained) and 27,254€/QALY. CONCLUSIONS: Cost-effectiveness and cost-utility ratios of belimumab compared to SoC treatment are below internationally applied thresholds. Belimumab can be considered as an add-on therapy to SoC for the treatment of SLE patients with highly active disease in Greece.