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Coagulase-negative staphylococci (CoNS) are frequent contaminants of blood cultures. We aimed to evaluate the systemic inflammatory response syndrome (SIRS) criteria in patients with CoNS bacteraemia for discrimination between true bloodstream infection (BSI) and contamination. Prospective evaluation was carried out of clinical and laboratory parameters in adults with at least one positive blood culture with CoNS at the University Hospital of Basel between 2003 and 2007. Of 3060 positive blood cultures, 654 episodes of CoNS bacteraemia were identified. Of these, 232 (35%) were considered to be true BSI and 422 (65%) were considered to be contamination. Overall, 80% of study participants had at least one SIRS criterion, fever being the most common, and 49% had at least two SIRS criteria. In the multivariate analysis, independent predictors of BSI were fever or hypothermia (OR 2.93, 95% CI 1.91-4.5), tachycardia (OR 2.29, 95% CI 1.50-3.50), tachypnoea (OR 2.4, 95% CI 1.30-4.43), leucocytosis or leucopenia (OR 4.15, 95% CI 2.17-6.36) and the presence of a central venous line (OR 5.38, 95% CI 3.25-8.88). The probability of BSI increased with each additional SIRS criterion, ranging from 42.4% in patients with only one SIRS criterion to 56.7% for those with two criteria, and 72.3% for patients with three SIRS criteria. A positive blood culture with CoNS most likely represents true BSI if the patient has at least three SIRS criteria or two SIRS criteria and a central venous catheter. These simple bedside criteria may guide decision to treat, decreasing the use of glycopeptides.