Background: The cerebrospinal fluid (CSF) culture is a widely used method for the diagnosis of meningitis, but its detection sensitivity is low. Several new methods have been developed for pathogen detection, including metagenomic next-generation sequencing (mNGS) and pathogen-targeted NGS (ptNGS). In this study, we aimed to evaluate the performance of ptNGS in pathogen detection in CSF. Methods: CSF specimens were acquired from 38 patients with meningitis who were diagnosed at Xuanwu Hospital of Capital Medical University between October 2020 and February 2021. DNA was extracted from the CSF samples, and pathogens were identified using both ptNGS and mNGS. SPSS 22.0 software was used to compare the pathogen detection performance of ptNGS and mNGS in CSF. Results: Among the 38 patients with meningitis, 14 had a non-infectious disease (NID) and 24 had an infectious disease (ID). Of the 38 samples, both ptNGS and mNGS detected 9 (23.7%) positive samples, and 12 (31.6%) negative samples. Thirteen (34.2%) samples were detected to be positive by ptNGS only, and 4 (10.5%) were detected to be positive by mNGS only. The positivity rate detected by ptNGS for the ID group was higher than that detected by mNGS (P=0.080), and the positivity rates detected by ptNGS and mNGS for the NID group were comparable. The positive predictive value (PPV) and negative predictive value (NPV) of diagnosing an ID by ptNGS were 70.8% and 64.3%, respectively. While, the PPV and NPV of diagnosing an ID by mNGS were 76.9% and 44.0%, respectively. ptNGS increased the sensitivity rate by approximately 85%. The sensitivity rate of ptNGS was higher than that of mNGS (77.3% vs. 41.7%), while the specificity rate of mNGS was higher than that of ptNGS (78.6% vs. 64.3%). Additionally, ptNGS required a shorter time for pathogen diagnosis (15 vs. 24 hrs) and had lower costs than mNGS. Conclusions: ptNGS has a number of advantages over mNGS, including its sensitivity, timeliness, and economy, all factors that are important considerations in clinical use.