Abstract: OBJECTIVE To observe the clinical efficacy of intrathecal injection of antibiotics in treatment of patients with intracranial infections after craniotomy so as to provide guidance for clinical treatment. METHODS A total of 80 patients with postoperative intracranial infections who underwent the craniotomy from May 2011 to Jun 2014 were enrolled in the study and randomly divided into the experimental group and the control group, with 40 cases in each. The experimental group was treated with intrathecal injection of vancomycin, while the control group was given the intravenous injection of antibiotics. The clinical efficacy, biochemical indicators of cerebrospinal fluid, treatment time, hospitalization cost, and incidence of adverse reactions were observed and compared between the two groups of patients, and the statistical analysis was performed with the use of SPSS 16.0 software. RESULTS In the experimental group, 21 patients were cured, 14 patients were cured, and 3 patients were effective; the total effective rate of the experimental group was 95.0%, significantly higher than 75.0% of the control group (P<0.05). The treatment time of the experimental group was significantly shorter than that of the control group; the hospitalization cost of the experimental group was significantly less than that of the control group (P<0.05). The incidence rate of adverse reactions was low in the experimental group and the control group, and there was no significant difference. CONCLUSION The intrathecal injection of antibiotics can significantly improve the clinical effect on treatment of the postoperative intracranial infections in the patients undergoing craniotomy, reduce the levels of white blood cells and protein in cerebrospinal fluid, and reduce the treatment time as well as the hospitalization cost, with the safety high.