Bloodstream infection (BSI) in hemodialysis (HD) patients is often difficult to diagnose. Systemic inflammatory response syndrome (SIRS) is a sensitive predictor of BSI in the general population. We aimed to assess the usefulness of SIRS in predicting BSI in HD patients. We designed a multicenter retrospective observational study of adult (age > 18 years) HD patients who underwent two sets of blood cultures for suspected BSI at first hospital visit from August 2011 to July 2012. Clinical, biological, and microbial data were evaluated to evaluate SIRS as a predictor of BSI upon initial presentation to the hospital. Data were obtained from 279 HD patients. Vascular access other than arteriovenous fistula and subcutaneously fixed superficial artery, and those administered antimicrobial drugs before visit were excluded; thus, a total of 202 patients were finally enrolled. Mean patient age was 71 years, 67.3% were male, 49.3% had diabetes, 28.2% had indwelling hardware, and 18.3% patients had BSI. Endocarditis and vertebral osteomyelitis were common infection sites, and Staphylococcus aureus was the most common pathogen. Of those with SIRS, 25.3% had BSI and 74.7% did not (odds ratio for SIRS, 2.10; 95% confidence interval, 0.90–4.91; p = 0.11). Thus, SIRS had a low sensitivity for predicting BSI in HD patients (sensitivity, 71.9%; specificity, 45.2%; positive likelihood ratio, 1.31; negative likelihood ratio, 0.62). Systemic inflammatory response syndrome has low sensitivity in identifying BSI in HD patients. A low threshold for drawing blood cultures and initiating antibiotic treatment should be considered for HD patients.