Introduction <p>Craniotomy is a frequent neurosurgical procedure; nosocomial infections following this can lead to additional risks in patients, increasing morbidity and causing fatal consequences.</p> Objectives <p>This work aimed to describe the primary nosocomial infections and identify the risk factors associated with nosocomial infections in patients undergoing craniotomy.</p> Methods <p>A quantitative retrospective study was developed. Data were collected from the digital clinical records system at Hospital III Daniel Alcides Carrión in Tacna. A multivariate analysis used Poisson regression with robust variance to determine independent risk factors.</p> Results <p>A total of 107 patients underwent craniotomy were included in the study, 49 patients (45.79%) developing at least one nosocomial infection. Our analysis identified several significant risk factors for the development of these infections, including admission to the critical care unit as a postoperative destination [RR = 2.34 (1.26–4.33), <i>p</i> = 0.007], hypertension [RR = 1.74 (1.07–2.83), <i>p</i> = 0.024], and the presence of perioperative antibiotic coverage [RR = 1.51 (1.05–2.17), <i>p</i> = 0.025]. The main types of nosocomial infections were pneumonia (63.27%), urinary tract infections (44.90%), bacteremia (16.33%), and ventriculitis (10.20%). The most frequently isolated pathogen was <i>Klebsiella pneumoniae</i>, accounting for 22.12% of the infections, followed by <i>Pseudomonas aeruginosa</i> (20.19%) and <i>Escherichia coli</i> (10.58%).</p> Conclusion <p>Our study demonstrates that admission to a critical care unit, hypertension, and perioperative antibiotic coverage are independent risk factors for nosocomial infections in post-craniotomy patients. These findings highlight the need for targeted prevention strategies to mitigate these risks and improve patient outcomes.</p>