Objective: Systemic lupus erythematosus (SLE) is a multi‐system inflammatory disease characterized by production of various autoantibodies. The aim of this study was to investigate the presence of anti‐ficolin‐2 antibodies in SLE patients and to evaluate the association between the levels of these autoantibodies, clinical manifestations, and disease activity. Methods: This is a comparative study using a cohort of 165 SLE patients and 48 healthy subjects. SLE patients were further divided into two groups, with “low disease activity” (SLEDAI score ≤ 4, n = 88) and with “high disease activity” (SLEDAI score > 4, n = 77). Clinical manifestations were defined according to the physician in charge. Active lupus nephritis (LN) was documented by kidney biopsy. Detection of anti‐ficolin‐2 antibodies was performed by ELISA. Results: Levels of the anti‐ficolin‐2 autoantibodies were significantly higher in SLE patients as compared to healthy subjects and associated with the SLEDAI score. They were found positive in 61/165 (37%) SLE patients. Presence of anti‐ficolin‐2 antibodies was significantly related only to renal involvement, with a very high prevalence (86%) of anti‐ficolin‐2 antibodies in SLE patients with active LN. Patients with active proliferative LN had significantly more positive anti‐ficolin‐2 antibodies than those with non‐proliferative LN. The combination of anti‐ficolin‐2, anti‐ficolin‐3 and anti‐C1q demonstrated a very high specificity (98%) for the diagnosis of active LN. Conclusion: Our results support the usefulness of anti‐ficolin‐2 as a complementary serological biomarker for the diagnosis of active lupus with renal manifestation