The risk of serious bacterial infectious events (SIEs) after an RTX course used in severe and refractory cases of systemic autoimmune diseases (SAID) is well known. Risk factors for SIEs merit investigation. For this case-control study, data were collected in a single centre of internal medicine and included all patients who received rituximab (RTX) for SAID between 2005 and 2011 (rheumatoid arthritis was excluded). Sixty-nine patients with SAID received a total of 87 RTX courses. Thirteen SIEs were reported in 12 patients leading to death in 5 patients. Patients with a history of SIE were significantly older (63.6±18.8 vs 48.8±16.7; p=0.0091), suffered most frequently of diabetes mellitus (33.3% vs 5.3%, p=0.015), had a lower CD19 count (1.0±1.2/mm3 vs 3.9±7.2/mm3) and had most frequently a prednisone dose>15 mg/day (91.7% vs 47.7%) at the start of the first RTX course. The SIE rate was 18.7 per 100 patient-years. At the initiation of the RTX course, risk factors for SIEs were lower IgG levels (OR=0.87, 95%CI=0.77-0.99, p=0.03), lower CD19 count (OR=0.85, 95%CI=0.73-1.00) and creatinine clearance≤45 ml/min (OR=7.78, 95%CI=1.36-44.38, p=0.002). Conversely history of pneumococcal vaccination significantly decreased the risk of SIEs (OR=0.11, 95%CI=0.03-0.41, p=0.0009). Concomitant treatment with prednisone at a dose>15 mg/day significantly increased the SIE risk (OR=8.07, 95%CI=1.94-33.59, p=0.0004). SIEs are frequent in SAID treated with RTX, particularly in patients receiving high-dose corticosteroids, in patients with renal insufficiency and in patients with low IgG levels or a low CD19 count.