The objective of this multicentric case-control study was to investigate if a history of autoimmune disease (AD) in first-degree relatives (FDR) is a risk factor for systemic lupus erythematosus (SLE) and to evaluate the risk of AD among FDR of SLE patients. Cases were Italian SLE patients consecutively enrolled. Controls were orthopaedic inpatients without any autoimmune diseases. The strength of the association between family history of AD and SLE was measured as an odds ratio (OR) calculated from the coefficient of an unconditional regression model. To calculate the risk of AD among FDR of SLE patients, the extended generalized estimating equation technique was used. In total, 154 SLE cases and 140 controls were enrolled. A family history of AD was reported by 22.7% of SLE patients and by 5.7% of the controls. The risk of SLE increased with the number of FDR with AD (one FDR affected, OR = 4.1; two or more, OR = 11.3). The probability of having AD was higher among FDR of SLE cases in comparison to FDR of controls (RR = 4.6; 95%CI 1.9-11.1). A female SLE patient conferred an increased risk of AD to her FDR; this risk is doubled in females (OR 10.3; 95% CI 3.1-34.4).