The research aimed to explore the role of cerebrospinal fluid heparin-binding protein in estimating the functional outcomes among patients with postcraniotomy meningitis or ventriculitis.Adult patients with meningitis or ventriculitis following craniotomy were eligible for this prospective observational cohort study conducted in the intensive care unit of a tertiary referral academic medical center. Patients were dichotomized by the Glasgow Outcome Scale score as good (4-5) and adverse functional outcome group (1-3) at hospital discharge. Heparin-binding protein, procalcitonin, white blood cell count, glucose, protein, and lactate in cerebrospinal fluid were tested at enrollment and on the 3rd to 5th day of antibiotherapy.Among 246 suspected participants, 139 with postcraniotomy meningitis or ventriculitis were enrolled in the final analysis, including 82 with good and 57 with adverse functional outcomes. Patients with adverse functional outcomes had significantly higher levels of heparin-binding protein than those with good functional outcomes. The protein descended significantly in patients with good functional outcomes on the 3rd to 5th day of antimicrobial treatment compared with baseline (29 [9-92] ng/mL vs. 136 [85-187] ng/mL). It was the only biomarker that remained high in the adverse functional outcome group on the 3rd to 5th day of treatment (209 [136-222] ng/mL vs. 170 [129-200] ng/mL at baseline). Heparin-binding protein achieved the highest area under the receiver operating characteristic curve of 0.86 (95% confidence interval 0.78-0.93) in recognizing patients with adverse functional outcomes. It was significantly associated with patient functional outcomes with an adjusted odds ratio of 1.02 (1.00-1.03), p = 0.01.Cerebrospinal fluid heparin-binding protein is a more accurate candidate biomarker in evaluating functional outcomes among patients with postcraniotomy meningitis and ventriculitis. Monitoring its kinetics helps to estimate antibacterial therapeutic efficacies.© 2025. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.