Background The differential diagnosis between postneurosurgical bacterial meningitis and aseptic meningitis remains challenging both for the clinician and the laboratory. Combinations of markers, as opposed to single ones, may improve diagnosis and thereby survival. Methods This prospective cohort study included patients with suspected bacterial meningitis after neurosurgery. The patients were divided into two groups according to the diagnostic criteria of meningitis involving a postneurosurgical bacterial meningitis group and a postneurosurgical aseptic meningitis group. Four biomarkers, including cerebrospinal fluid procalcitonin, lactate, interleukin-8 and interleukin-10 were assayed separately, and three algorithms were constructed using a linear combination. The area under the receiver operating characteristic curve was used to compare their performances. Results A cohort of 112 patients was enrolled in our study. Forty-three patients were diagnosed with postneurosurgical bacterial meningitis, and the cerebrospinal fluid values of their biomarkers were higher in patients with postneurosurgical bacterial meningitis than with postneurosurgical aseptic meningitis. The area under the receiver operating characteristic curves for the detection of postneurosurgical bacterial meningitis were 0.803 (95% confidence interval [CI], 0.724-0.883) for procalcitonin; 0.936 (95% CI, 0.895-0.977) for lactate; 0.771 (95% CI, 0.683-0.860) for interleukin-8; 0.860 (95% CI, 0.797-0.929) for interleukin-10; 0.937 (95% CI, 0.897-0.977) for the composite two-marker test; 0.945 (95% CI, 0.908-0.982) for the composite three-marker test and 0.954 (95% CI, 0.922-0.989) for the composite of all tests. The area under the receiver operating characteristic curves of the combination tests were greater than those of the single markers. Conclusions Combining information from several markers improved the diagnostic accuracy in detecting postneurosurgical bacterial meningitis.