The study aimed to identify factors predicting response to belimumab treatment in phase 3 BLISS trials for autoantibody-positive systemic lupus erythematosus (SLE) and to analyze clinical efficacy in various patient subsets. The BLISS trials compared belimumab 1 and 10 mg/kg versus placebo, all plus standard SLE therapy, over 52 or 76 weeks. Pooled subgroup analyses based on demographic characteristics and baseline disease activity indicators were performed. Key factors associated with an increased benefit of belimumab included SELENA–SLEDAI ≥10, low complement, anti-dsDNA positivity, and corticosteroid use. Efficacy outcomes were assessed in subgroups with low complement/anti-dsDNA positivity and SELENA–SLEDAI ≥10. Week 52 SLE Responder Index rates were significantly higher with belimumab compared to placebo in these subgroups. Further analysis showed that belimumab produced greater benefits regarding severe flares, corticosteroid use, and health-related quality of life in the low complement/anti-dsDNA-positive subgroup. The findings suggest that belimumab has greater therapeutic benefit in patients with higher disease activity, anti-dsDNA positivity, low complement, or corticosteroid treatment at baseline.The study aimed to identify factors predicting response to belimumab treatment in phase 3 BLISS trials for autoantibody-positive systemic lupus erythematosus (SLE) and to analyze clinical efficacy in various patient subsets. The BLISS trials compared belimumab 1 and 10 mg/kg versus placebo, all plus standard SLE therapy, over 52 or 76 weeks. Pooled subgroup analyses based on demographic characteristics and baseline disease activity indicators were performed. Key factors associated with an increased benefit of belimumab included SELENA–SLEDAI ≥10, low complement, anti-dsDNA positivity, and corticosteroid use. Efficacy outcomes were assessed in subgroups with low complement/anti-dsDNA positivity and SELENA–SLEDAI ≥10. Week 52 SLE Responder Index rates were significantly higher with belimumab compared to placebo in these subgroups. Further analysis showed that belimumab produced greater benefits regarding severe flares, corticosteroid use, and health-related quality of life in the low complement/anti-dsDNA-positive subgroup. The findings suggest that belimumab has greater therapeutic benefit in patients with higher disease activity, anti-dsDNA positivity, low complement, or corticosteroid treatment at baseline.