The pharmacokinetic/pharmacodynamic (PK/PD) parameter for evaluating the efficacy of vancomycin is now recommended to target an AUC/MIC (area under the curve, AUC; minimum inhibitory concentration, MIC) ratio of 400 to 600, and trough concentration should not be used as a substitute. We report a case of intracranial infection caused by methicillin-resistant Staphylococcus epidermidis (MRSE), which was sensitive to vancomycin (MIC=2µg/mL) and linezolid (MIC=4µg/mL). The trough concentration of vancomycin in serum was 18.3 µg/mL, and the vancomycin concentration in CSF was 5.0 µg/mL, all within normal range. However, the AUC/MIC ratio was calculated to be 125 mg·h·L-1, unable to reach target AUC/MIC. Vancomycin was replaced with linezolid after 36 days of treatment due to poor outcome, and the patient was eventually cured. Further, 23 cases of intracranial methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant coagulase-negative Staphylococcus (MRCoNS) infections were reported, of which 1 case with MRSA had a vancomycin MIC of 1 µg/mL, while the remaining 22 cases had vancomycin MICs >1 µg/mL. The linezolid-containing regimen was used after drug susceptibility results or if the initial treatment failed, leading to recovery in 19 patients, microbial clearance in 3 patients, and treatment failure in 1 case. In conclusion, vancomycin dosing should be based on AUC-guided dosing and monitoring. When the vancomycin MIC of MRSA/MRCoNS is >1 µg/mL, the target AUC/MIC may not be achieved. In such cases, linezolid can effectively be considered as a good alternative to vancomycin.