Recent studies point to a dual role for galectin-3 as both a circulating damage-associated molecular pattern and a cell membrane-associated pattern recognition receptor. The aim of this study was to assess the potential of circulating galectin-3 for discriminating between infections and non-infectious inflammatory disorders on the one hand, and between fungal and bacterial infections on the other. Galectin-3 and C-reactive protein (CRP) were measured in the plasma of 127 patients with either non-infectious inflammatory disorders (gout, autoinflammatory syndrome or pancreatitis) or an infection (viral lower respiratory tract infection, bacterial sepsis or candidaemia). Circulating galectin-3 concentrations were increased in patients with infections when compared with healthy volunteers or patients with non-infectious inflammatory diseases. At cut-off values with a specificity of 95%, the sensitivity of galectin-3 (>20.6 ng/ml) to discriminate between an infection and non-infectious inflammation was higher than that of CRP (>156 mg/l): 43% [95% confidence interval (CI) 33-53%] versus 27% (95% CI 19-37%), p = 0.03. After exclusion of patients with CRP <156 mg/l, galectin-3 concentration >20.6 ng/ml could identify 41 % (95% CI 29-53%) of the patients with an infection at the cost of one false-positive with non-infectious inflammation. Using this sequential approach, 57% of the patients with an infection could be selected. Galectin-3 concentrations were similar in patients with bacterial and Candida sepsis, while being lower in viral respiratory infections. Although galectin-3 does not discriminate between bacterial and Candida sepsis, the sequential use of CRP and galectin-3 in distinguishing infectious diseases from non-infectious inflammation may be superior to CRP alone.