Objectives: Fever has been recently included in the new 2019 EULAR/ACR classification criteria for Systemic Lupus Erythematosus (SLE). Thus, we investigated the possible association of fever with other clinical disease manifestations. Secondly, we analyzed a panel of 30 SNPs to verify their possible contribution to the pathogenesis of this constitutional symptom. Methods: In this retrospective study we collected clinical/laboratory features in a SLE cohort, including the occurrence of fever (body temperature >37.5°C, excluding infective etiology). A phenotype-genotype correlation analysis was carried out. Results: We evaluated 167 patients (M/F 12/155, median age at the disease diagnosis 30 years, IQR 17; median disease duration 240 months, IQR 156). Seventy patients (41.9%) reported fever, significantly associated with: serositis and hematological manifestations (p=0.02 and p=0.00001, respectively). A significant association between fever and leukopenia (p=0.0029), hemolytic anemia (p=0.04), and thrombocytopenia (p=0.03) was observed. In addition, significantly higher median SDI values were observed in patients with fever in comparison with those without [2 (IQR 3) vs 1 (IQR 2); p= 0.005). The genotype/phenotype analysis showed an association between fever and IRGM rs13361189 (p=0.003; OR 3.89, CI 1.16-13.03), confirmed also in multivariate logistic regression analysis (p=0.028, r=1.39). Conclusions: We identified a specific disease phenotype characterized by fever, hematological manifestations, serositis, and more severe chronic damage. Moreover, we found the association between IRGM rs13361189 polymorphism and the occurrence of inflammatory fever, potentially providing new insights into the role of genetic background in the pathogenesis of SLE-related fever.