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This study aimed to address whether bloodstream infections are a risk factor for the development of severe lupus flares, as well as clinical, immunological and microbiological features of patients with bloodstream infections that develop severe lupus flares. Methods: We performed a retrospective cohort study comparing 87 systemic lupus erythematosus (SLE) patients with bloodstream infections and 87 hospitalized SLE patients without bloodstream infections as a comparison group. All patients were followed up for at least 3 months or until one of the primary outcomes was developed (severe SLE flare according to SELENA/ SLEDAI score or death). Microbiological features of all bloodstream infections were recorded. The disease status at the end of follow up was registered. Results: A total of 23 patients (13.2%) developed a severe flare during follow up; among them, 20 (87%) had an associated episode of bloodstream infection (p<0.001). The most frequent flares were renal (43.4%) and severe thrombocytopenia (26%). After multivariate analysis, baseline-independent factors associated with severe SLE flare were bloodstream infection [hazard ratio (HR) 7.3, 95% confidence interval (CI) 2.13-24.95; p=0.002]. Among patients with bloodstream infections, low C4 levels (HR 2.43, 95% CI 1.04-5.69: p=0.04) and Streptococcus pneumoniae were associated with severe SLE flare (HR 3.41, 95% CI 1.68-6.91; p=0.012). Conclusions: SLE patients with bloodstream infections, especially due to S. pneumoniae, and low C4 levels, are at higher risk for development of severe SLE flares. [ABSTRACT FROM AUTHOR]