Here, we report an original fluorescence pattern on HEp2000TM-cells defined as nuclear speckled with diffuse cytoplasmic pattern and perinuclear enhancement that is related to P. falciparum infection. Its recognition recently allowed the diagnosis to malaria in several patients at our center. We also show that polyclonal autoantibodies of IgG isotype are responsible for this pattern recognizing autoantigens with high homology with plasmodium proteins. Although the symptoms of acute malaria are generally recognized by trained physicians, malaria may be overlooked when the patients have Epoxomicin visited or left endemic areas months or years before. The risk of missing the diagnosis is even higher when malaria adopts a smoldering form like chronic carriage, gestational malaria or HMS. In these situations the clinical presentation is subacute or chronic, and conventional parasitological tests may be negative. These patients are therefore sometimes investigated for several days or weeks in internal medicine or other settings for fatigue, splenomegaly, anemia, cytopenia, hemophagocytic syndrome, or can be mistakenly splenectomized with a suspicion of splenic lymphoma. We show here that a distinct nucleo-cytoplasmic pattern on indirect immunofluorescence i.e. cytoplasmic diffuse, nuclear speckled with perinuclear enhancement fluorescence while searching for ANA can efficiently reorient the diagnosis toward malaria. Rapid confirmation of the diagnosis is then with antimalarial serology or amplification of P. falciparum nucleic acids. Our prospective analysis in 10,400 patients confirms that even a patient with unknown history of malaria is likely to have a smoldering form of malaria if his serum displays the nucleo-cytoplasmic malariarelated pattern when searching for ANA. Indeed, 15 of 19 sera displaying the malaria-related pattern were from patients with either past or active malaria. Although some patients with the distinct nucleo-cytoplasmic pattern had a previously cured infection, we uncovered four active infections not previously reported in the clinical files or disclosed by the patient. Even more importantly, the pattern revealed among the latter unexpected diagnosis of ongoing gestational malaria in two patients and active HMS in one. Preliminary results in three patients suggest that P. malariae, and P. ovale may induce the same nucleo-cytoplasmic malaria-related pattern in the ANA test. Detection of ANA is routinely performed for the diagnosis of systemic autoimmune diseases such as SLE. While the detection of autoantibodies recognizing components of the nucleus have been extensively tested for more than 50 years, autoantibodies recognizing components of the cytoplasm have not drawn much attention until the identification in the late 809s of antiribosome autoantibodies in SLE and anti-Jo1 autoantibodies in inflammatory myositis. Other distinct cytoplasmic patterns have been also associated with autoantibodies found in other autoimmune myositis and in primary biliary cirrhosis . Thus both nuclear and cytoplasmic patterns can orient the diagnosis toward autoimmune diseases.