IL-36 cytokines (IL-36Ra, IL-36α, IL-36β and IL-36γ) belong to the IL-1 family and have been linked to several autoimmune diseases. However, little is known about the relationships between systemic lupus erythematosus (SLE) and IL-36 cytokines. In this study, serum IL-36 cytokine levels were determined by enzyme-linked immunosorbent assay (ELISA), and their associations with SLE-related parameters were analyzed in 72 SLE patients and 63 healthy controls. Additionally, IL-36 cytokine mRNA levels were assessed in 30 of 72 SLE patients and 20 of 63 healthy controls using real-time quantitative reverse transcription polymerase chain reaction (RT-PCR). Compared to healthy controls, SLE patients had significantly decreased serum IL-36Ra levels (P = 0.001) and markedly increased serum IL-36α and IL-36γ levels (P = 0.004 and P = 0.001, respectively). Serum IL-36α and IL-36γ levels were significantly higher in active SLE patients [SLE Disease Activity Index (SLEDAI) score ≥ 5] than in inactive patients (SLEDAI score ≤ 4) (P = 0.020 and P = 0.017, respectively). Serum IL-36α and IL-36γ levels were strongly correlated with SLEDAI score (r = 0.308, P = 0.008 and r = 0.400, P = 0.001, respectively) and complement C3 levels (r = −0.276, P = 0.019 and r = −0.314, P = 0.007, respectively). Moreover, SLE patients with arthritis had significantly higher serum IL-36α and IL-36γ levels than those without arthritis (P = 0.001 and P < 0.001, respectively). Our study indicates that the imbalanced antagonist/agonist profile of IL-36 cytokines may be linked to SLE pathogenesis. Furthermore, IL-36α and IL-36γ may participate in arthritis and may be good biomarkers of SLE disease activity.