Abstract Objectives: To evaluate belimumab effectiveness and safety in real-life Portuguese patients with Systemic Lupus Erythematosus (SLE). Materials and Methods: Multicenter cohort study including all SLE patients treated with belimumab in seven Portuguese rheumatology centers. Demographic, clinical and serological data were collected at baseline, 6, 12 and 24 months of treatment with belimumab. To evaluate effectiveness we used SLE Responder Index (SRI) rates and changes in SELENA-SLEDAI. Safety was evaluated by the number of adverse events. Results: Thirty-eight patients were included: 37 (97.4%) female, with a mean age of 46.2±13.9 years. Mean SELENA-SLEDAI was 8.2±3.9, 78.8% had elevated anti-double-stranded DNA (anti-dsDNA) antibodies and 72.7% had complement consumption at baseline. Multiorgan involvement was the leading cause for the use of belimumab. SRI response was achieved in 51.9%, 60% and 91.7% at 6, 12 and 24 months of belimumab treatment, respectively. LUNDEX adjusted SRI response rates were 45.4%, 45.0% and 45.8% at 6, 12 and 24 months of belimumab, respectively. Mean SELENA-SLEDAI, anti-dsDNA antibodies and daily prednisolone dosage decreased significantly from baseline to 6, 12 and 24 months and C3 levels increased significantly at 12 months of belimumab treatment. Five patients presented adverse events (infections in three cases) and eleven patients discontinued belimumab (four due to inefficacy, three due to adverse events and four were lost to follow-up). Conclusions: Our study confirmed, in real-life Portuguese patients with active SLE, the effectiveness of belimumab in reduction of disease activity, immunological response and steroid-sparing, with a good safety profile.