Background: Previous studies reported higher interleukin-6 (IL-6) levels in systemic lupus erythematosus (SLE) patients than in healthy controls. However, the clinical relevance of IL-6 in SLE has not been clearly established. Aim of the work: The present study aimed to evaluate the clinical significance of serum and urinary IL-6 and their usefulness as markers of disease activity in SLE. Patients and methods: 63 SLE patients were included. Disease activity was assessed according to the Systemic Lupus Activity Measure (SLAM) score. Serum and urinary IL-6 were assessed by ELISA. Results: The study included 63 Romanian patients, female to male ratio 9.5:1 with a mean age of 45.4 ± 12.6 years and disease duration of 8 (3–12.3) years. The median SLAM score at inclusion was 5 (range 3–8). Urinary IL-6 significantly correlated with proteinuria (r = 0.25; p = 0.04) and negatively with the platelet count, C3 and C4 levels (r = −0.38; p = 0.002, r = −0.43; p = 0.001, and r = −0.46; p < 0.001 respectively). Moreover, in patients with active lupus nephritis (LN), urinary IL-6 correlated with the SLAM (r = 0.62; p = 0.01). Patients with low urinary IL-6 levels (<7.3 pg/ml) had a longer duration of treatment with corticosteroids or hydroxychloroquine (HCQ) (9.5 vs 4 years; p = 0.02 and 7 vs 4 years; p = 0.02). In a regression, only C3 was a significant determinant of urinary IL-6 level. Conclusions: Urinary but not serum IL-6 seems to be related to SLE activity in LN patients. Treatment with corticosteroids or HCQ therapy might reduce urinary IL-6 levels in SLE.