Neurosurgery is characterized by a prolonged risk period for surgical site infection (SSI), mainly related to the presence of cerebrospinal fluid (CSF) drains. We aimed to examine factors associated with post-neurosurgical SSIs, focusing on post-operative factors. A prospective cohort study was conducted in a single center over a period of 18 months in Israel. Included were adult patients undergoing clean or clean-contaminated craniotomy, including craniotomies with external CSF drainage or shunts. SSIs were defined by the Centers for Disease Control and Prevention (CDC) criteria for healthcare-associated infections. All patients were followed up for 90 days and those with foreign body insertion for 1 year. We compared patients with and without SSI. A multivariable regression analysis for SSI was conducted including uncorrelated variables significantly associated with SSI. A total of 502 patients were included, with 138 (27.5%) undergoing emergent or urgent craniotomy. The overall SSI rate was 5.6% (28 patients), of which 3.2% (16 patients) were intracerebral. Non-elective surgery, external CSF drainage/monitoring devices, re-operation, and post-operative respiratory failure were independently associated with subsequent SSI. External CSF devices was the only significant risk factor for intracerebral SSIs (p < 0.001). Internal shunts or other foreign body insertions were not associated with SSIs. A phenotypically identical isolate to that causing the SSI was isolated from respiratory secretions prior to the SSI in 4/9 patients with microbiologically documented intracerebral SSIs. Patients with SSIs had longer hospital stay, poorer functional capacity on discharge, and higher 90-day mortality. We raise the possibility of post-operative infection acquisition through external CSF devices. Standard operating procedures for their maintenance are necessary.