Belimumab is a B lymphocyte stimulator (BLyS) inhibitor used in the treatment of systemic lupus erythematosus (SLE). The BLISS trials, which compared belimumab 1 and 10 mg/kg with placebo in patients with autoantibody-positive SLE, showed that belimumab, when combined with standard therapy, significantly improved SLE Responder Index (SRI) rates compared to standard therapy alone. The SRI measures improvement in disease activity, with a 4-point decrease in SELENA-SLEDAI score being considered clinically meaningful. Baseline factors associated with a greater response to belimumab included SELENA-SLEDAI scores of 10 or greater, low complement levels, anti-dsDNA positivity, and corticosteroid use. Patients with low complement/anti-dsDNA positivity and SELENA-SLEDAI scores of 10 or greater had the highest response rates to belimumab. In the low complement/anti-dsDNA-positive subgroup, SRI rates at week 52 were 31.7% with placebo, 41.5% with belimumab 1 mg/kg, and 51.5% with belimumab 10 mg/kg. In the SELENA-SLEDAI ≥10 subgroup, the rates were 44.3%, 58.0%, and 63.2%, respectively. Belimumab also reduced the risk of severe flares, corticosteroid use, and improved health-related quality of life (HRQoL). In the low complement/anti-dsDNA-positive subgroup, belimumab significantly reduced corticosteroid use and the risk of severe flares. The 10 mg/kg dose showed greater benefits than the 1 mg/kg dose. Belimumab was also associated with greater improvements in HRQoL measures, including the Functional Assessment of Chronic Illness Therapy–Fatigue scale and the Short Form 36 health survey physical component summary scores. Safety data showed similar adverse event rates between belimumab and placebo in the low complement/anti-dsDNA-positive subgroup. Serious adverse events were somewhat more common with belimumab, but there was no excess of adverse events in any individual system organ class. The findings suggest that belimumab has greater therapeutic benefit than standard therapy alone in patients with higher disease activity, anti-dsDNA positivity, low complement levels, or corticosteroid treatment at baseline. These results support the use of belimumab in patients with high disease activity and may help identify SLE disease characteristics that enhance the potential for response to biological therapies.Belimumab is a B lymphocyte stimulator (BLyS) inhibitor used in the treatment of systemic lupus erythematosus (SLE). The BLISS trials, which compared belimumab 1 and 10 mg/kg with placebo in patients with autoantibody-positive SLE, showed that belimumab, when combined with standard therapy, significantly improved SLE Responder Index (SRI) rates compared to standard therapy alone. The SRI measures improvement in disease activity, with a 4-point decrease in SELENA-SLEDAI score being considered clinically meaningful. Baseline factors associated with a greater response to belimumab included SELENA-SLEDAI scores of 10 or greater, low complement levels, anti-dsDNA positivity, and corticosteroid use. Patients with low complement/anti-dsDNA positivity and SELENA-SLEDAI scores of 10 or greater had the highest response rates to belimumab. In the low complement/anti-dsDNA-positive subgroup, SRI rates at week 52 were 31.7% with placebo, 41.5% with belimumab 1 mg/kg, and 51.5% with belimumab 10 mg/kg. In the SELENA-SLEDAI ≥10 subgroup, the rates were 44.3%, 58.0%, and 63.2%, respectively. Belimumab also reduced the risk of severe flares, corticosteroid use, and improved health-related quality of life (HRQoL). In the low complement/anti-dsDNA-positive subgroup, belimumab significantly reduced corticosteroid use and the risk of severe flares. The 10 mg/kg dose showed greater benefits than the 1 mg/kg dose. Belimumab was also associated with greater improvements in HRQoL measures, including the Functional Assessment of Chronic Illness Therapy–Fatigue scale and the Short Form 36 health survey physical component summary scores. Safety data showed similar adverse event rates between belimumab and placebo in the low complement/anti-dsDNA-positive subgroup. Serious adverse events were somewhat more common with belimumab, but there was no excess of adverse events in any individual system organ class. The findings suggest that belimumab has greater therapeutic benefit than standard therapy alone in patients with higher disease activity, anti-dsDNA positivity, low complement levels, or corticosteroid treatment at baseline. These results support the use of belimumab in patients with high disease activity and may help identify SLE disease characteristics that enhance the potential for response to biological therapies.