A post-operative central nervous system infection (PCNSI) is a dangerous complication after cranial surgery. Although a large number of neurosurgical procedures are performed in hospitals in China, PCNSI-related data from this country are rarely reported. To address this issue, we examined the incidence of PCNSI after cranial surgery, the potential risk factors, and the offending etiologic agents in a large Chinese population. The medical records and post-operative courses for patients >16 years of age who underwent elective or emergency cranial surgeries between May 2010 and May 2012 and who survived for >7 days were reviewed retrospectively. Pre-operative data, surgery-related records, and post-operative variables were evaluated as risk factors for PCNSI after cranial surgery. Among 1,470 surgeries, 1,340 were craniotomies and 130 involved the cerebrospinal fluid (CSF). There were 109 patients with PCNSIs, resulting in a total infection rate of 7.4 %. The dominant Gram-positive organism isolated (Staphylococcus aureus) was the most common pathogen isolated. Based on multivariate analysis, the risk of PCNSI was increased by a CSF leak [odds ratio (OR), 3.545; 95 % confidence interval (CI), 2.053-6.122; p < 0.001], CSF drainage of any kind (OR, 2.858; 95 % CI, 1.577-5.181; p = 0.001), subsequent short-term surgery (OR, 2.224; 95 % CI, 1.229-4.024; p = 0.008), and surgery duration (OR, 1.331; 95 % CI, 1.230-1.440; p < 0.001). PCNSI remains a critical problem for neurosurgeons in China. CSF leakage, CSF drainage of any kind, subsequent short-term surgery, and surgery duration were major risk factors, indicating that surgery-focused management might be the most effective way to minimize the risk for PCNSI after cranial surgery.