Nosocomial surgical-site infection (NSSI) after craniotomy is responsible for an increase in deaths and/or disabilities that affect quality of life. It is necessary to identify factors to be included in an index for their control. The aim of this study was to a) identify intrinsic and extrinsic factors associated with NSSI after craniotomy and b) obtain the infection risk attributed to both intrinsic and extrinsic factors as well as to compare their predictive capability with the NNISS (National Nosocomial Infection Surveillance System) index. A case-control study was conducted during a 2-year period in patients who underwent craniotomy in hospitals affiliated with the Instituto Mexicano del Seguro Social. Patients were selected according to the Centers for Disease Control and Prevention criteria for NSSI. During the study period 737 craniotomies were performed, 41 of which presented with NSSI. Intrinsic factors associated with NSSI were the presence of chronic diseases (OR = 2.18) and craniotomy due to nontraumatic causes (OR = 1.87), whereas extrinsic factors were procedures performed during the late shift (OR = 2.6) and another surgery at the same surgical site (OR = 5.2). These factors comprised the index with intrinsic and extrinsic factors. Extrinsic factors were 1.7 times higher than intrinsic factors, in addition to having a larger area under the ROC curve (0.731). The risk obtained with the NNISS index for patients who had one factor was 1.5, whereas that for patients who had two or three factors was 4.7. In the studied population, patients who underwent a craniotomy with extrinsic factors showed a higher association with NSSI.