Overproduction of inflammation-related cytokines plays an important role in systemic lupus erythematosus (SLE). A crucial cytokine is IL-18, a member of the IL-1 family involved in the regulation of both innate and acquired immune responses. The aim of this study was to evaluate free IL-18 levels in the serum and urine of SLE patients, in order to establish their relationship with other biomarkers of disease activity. Serum and urine levels of IL-18 and IL-18BP were measured by ELISA in 50 SLE patients and in 32 healthy subjects; free IL-18 was calculated using the law of mass action. Serum levels of total IL-18, IL-18BP and free IL-18 were higher in SLE patients than in healthy controls. Total and free serum IL-18 levels were higher in patients with active disease (with nephritis or active non-renal disease), and correlated with the ECLAM score. Urinary levels of total and free IL-18 were higher in patients than in controls, but did not correlate with disease activity. The data collected in this study show that increased levels of both IL-18 and its natural inhibitor IL-18BP, characterise SLE. Despite the overproduction of IL-18BP, free IL-18 is still significantly higher in SLE patients than in controls, and its serum levels are a marker of disease activity.