Objective. To investigate effectiveness and safety of belimumab in patients with active systemic lupus erythematosus (SLE) in a clinical practice setting. Methods. Sixty-seven patients with active SLE, mean 6 SD age 39.3 6 10.2 years, from 2 Italian prospective cohorts were treated with belimumab (10 mg/kg on day 0, 14, 28, and then every 28 days) added to background therapy. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), the Systemic Lupus International Collaborating Clinics/ American College of Rheumatology Damage Index, the Disease Activity Score in 28 joints (DAS28), 24-hour proteinuria, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score, anti-double-stranded DNA (antidsDNA), C3 and C4 levels, and prednisone daily dose were recorded at baseline, month 3, 6, 9, 12, 18, and 24. Arthritis was subdivided into "classical" (CLP) and "rheumatoid-like"; skin manifestations into acute (ACLE), subacute (SCLE), and chronic. SLE flares, defined according to the SLEDAI Flare Index, were calculated before and after belimumab initiation. Adverse events were carefully evaluated during treatment. Statistics were performed by the SPSS package (version 21.0). Results. Mean 6 SD followup was 16.2 6 9.5 months. Main refractory manifestations treated with belimumab were musculoskeletal (37.3%), mucocutaneous (22.4%), and renal (23.9%). SLEDAI-2K, prednisone daily dose, anti-dsDNA, DAS28, CLASI, and 24-hour proteinuria decreased during treatment. DAS28 score decreased in patients with polyarthritis (P < 0.001), particularly in those with CLP (P < 0.001), and CLASI decreased in patients with skin manifestation (P 5 0.003), either ACLE (P 5 0.051) or SCLE (P 5 0.047). Flare rate was lower 1 and 2 years after belimumab initiation than in the periods before (P 5 0.001). Belimumab was well-tolerated and no damage accrual was observed after initiation. Conclusion. Belimumab was effective and safe in a clinical practice setting; it decreased the number of flares and hindered damage progression in patients with active SLE.