Infections are an important cause of morbidity and mortality in Systemic Lupus Erythematosus (SLE). Mediterranean spotted fever (MSF) is a tick-borne disease caused by Rickettsia conorii. This infection is endemic in Tunisia with summer seasonality. Herein, the case of a 45 years old woman, admitted to hospital with fever and erythema nodosum. On examination, she had a diffuse skin rash, malar rash, and polyarthritis. Serology demonstrated Rickettsia Conoriiinfection. The diagnosis of MSF was made and the patient had a course of doxycycline for 5 days with a prompt improvement of the fever, the skin lesions but she had a persistent malar rash, polyarthritis, and lymphopenia. The immunological profile was positive for antinuclear antibodies (ANA), anti-DNA antibodies, anti-nucleosomes antibodies, and anti-citrullinated protein antibodies (ACPA). The diagnosis of SLE was established. We report the first case of SLE associated with MSF and with erythema nodosum as the initial presentation.