Antinuclear antibodies (ANA) are the most common autoantibodies in SLE, with a positive rate of up to 95-100%, but are not highly specific and can be used as screening autoantibodies for SLE. A small percentage of patients who meet the diagnostic criteria for SLE are clinically persistently negative for ANA; this group accounts for about 2% of all SLE patients and is known as a subtype of SLE. This may be due to the absence of ANA production; the binding of autoantibodies to affected tissues (e.g., skin or kidney tissue) or because they are hidden in circulating immune complexes; the use of adrenocorticotropic hormones and immunosuppressive drugs; or hypoproteinemia due to increased depletion of the renal basement membrane as the disease enters the end stage of nephropathy and large amounts of protein are excreted in the urine. It was found that non-specific damages such as fever, weight loss, arthralgia, myalgia, Raynaud’s phenomenon, oral ulcers, hair loss and other systemic damages were not significantly different in ANA-negative SLE patients compared with ANA-positive SLE patients; the incidence of butterfly erythema and photosensitivity was slightly higher but not significantly different; the incidence of hand and foot erythema was significantly higher than that of ANA-positive SLE patients, and skin damage was a significant feature of ANA-negative SLE. The incidence of anti-Ro/SSA antibodies in the serum of ANA-negative SLE patients was higher, and many studies showed that anti-Ro/SSA antibodies were closely related to photosensitivity, suggesting that anti-SSA antibodies and anti-SSB antibodies are important for the diagnosis of SLE and SCLE when ANA-negative is detected by indirect immunofluorescence. anti-dsDNA and anti-Sm antibodies in the serum of ANA-negative SLE patients were positive. The lower rate of positive anti-dsDNA and anti-Sm antibodies in the sera of ANA-negative SLE patients may be related to the lower chance of renal and hematologic damage in ANA-negative SLE patients and the fact that most of them are in the quiescent phase. Overall ANA-negative SLE patients have less systemic damage and a better prognosis. In patients with clinically suspected SLE and negative ANA test, attention should be paid to the detection of other target antigen-specific autoantibodies in the ANA spectrum, such as anti-SSA/Ro antibody, anti-SSB/La antibody, anti-ribosomal P protein (rRNP) antibody, anti-nucleosome antibody, anti-dsDNA antibody, etc. Attention should also be paid to the detection of other SLE-related autoantibodies, such as lupus anticoagulant, anti-cardiolipin antibody, anti-β 2GPI antibodies, anti-C1q antibodies, etc.