The aim of the study was to evaluate and compare the diagnostic value of sCD163 serum levels with CRP and PCT in meningitis and bacterial infection. An observational cohort study was conducted between February 2001 and February 2005. The study population comprised 55 patients suspected of meningitis on admission to a 27-bed infectious disease department at a Danish university hospital. Biomarker serum levels on admission were measured. Sensitivity and specificity were evaluated at pre-specified cut-off values and overall diagnostic accuracies were compared using receiver-operating characteristic AUCs (areas under curves). Patients were classified by 2 sets of diagnostic criteria into: A) purulent meningitis, serous meningitis or non-meningitis, and B) systemic bacterial infection, local bacterial infection or non-bacterial disease. An elevated serum level of sCD163 was the most specific marker for distinguishing bacterial infection from non-bacterial disease (specificity 0.91; sensitivity 0.47). However, the overall diagnostic accuracy of CRP (AUC =0.91) and PCT (AUC =0.87) were superior (p<0.02 and p<0.06) compared to that of sCD163 (AUC =0.72). For the diagnosis of systemic bacterial infection, the AUC of sCD163 (0.83) did not differ significantly from those of CRP or PCT. All markers had AUCs <0.75 for differentiating between purulent meningitis and other conditions. In conclusion, CRP and PCT had high diagnostic value and were superior as markers of bacterial infection compared to sCD163. However, sCD163 may be helpful in rapid identification of patients with systemic bacterial infection. If used as an adjunct to lumbar puncture, PCT and CRP had very high diagnostic accuracy for distinguishing between bacterial and viral infection in patients with spinal fluid pleocytosis. However, none of the markers was useful as an independent tool for the clinical diagnosis of patients with purulent meningitis.