Transforming growth factor beta (TGF-β) is a highly pleiotropic cytokine that has broad anti-inflammatory and immunosuppressive effects. In patients with systemic lupus erythematosus (SLE), the immunosuppressive effect of TGF-β1 is thought to be dysfunctional. In the present work, we aimed to study the relationship between the serum levels of TGF-β1 with the characteristics of the disease as well as with the patterns of activity, damage, or severity of the disease. Two hundred and eighty-four patients with well-characterized SLE were recruited. The serum levels of TGF-β1 were assessed. A multivariable linear regression analysis was performed to analyze the relation of disease characteristics to TGF-β1. The Katz severity index (beta coefficient 179 95% confidence interval 7-350 pg/mL, = 0.041) and SLEDAI activity index (beta coefficient 96 95% CI 20-171 pg/mL, = 0.014) were associated with higher serum levels of TGF-β1 after the multivariable analysis. When the disease-specific features were studied, ocular and cardiovascular manifestations were positively associated with serum TGF-β1 levels. In contrast, gastrointestinal and musculoskeletal involvements were associated with lower levels of circulating TGF-β1. Among patients with SLE, the serum levels of TGF-β1 were highly associated with disease-related manifestations.