Objectives To examine trend, prevalence, and outcomes of surgical site infection (SSI) in head and neck surgery. Study Design Retrospective cross-sectional analysis. Setting The Nationwide Readmissions Database (2010-2014), which represents 56.6% of all US hospitalization. Subjects Adult patients (≥18 years) who underwent head and neck surgery. Patients with SSI were compared with controls. Methods Analysis included chi-square test and multivariate logistic and linear regression models. Results A total of 427 cases and 116,921 controls were identified. SSI prevalence among patients who underwent head and neck surgery was 0.37%, of which 41.0% was reported within the initial admission while the remaining 59.0% was reported on readmission within 30 days of first surgery. SSI was associated with a higher mortality risk (odds ratio, 3.95; 95% CI, 1.25-12.50; P = .019). Multivariate analysis demonstrated that a higher risk of SSI was associated with major surgery of the ear, nose and paranasal sinuses, mouth and tonsil, salivary glands and ducts, maxillofacial bones and mandible, and pharynx and larynx ( P < .05 each). However, a lower risk of SSI was reported in thyroid and parathyroid and nonmajor procedures ( P < .05 each). Other factors associated with a higher risk of SSI included multiple comorbidities, smoking, cancer diagnosis, concomitant neck dissection, and tracheostomy ( P < .05 each). SSI was associated with a mean ± SE additional hospital stay of 8.1 ± 0.8 days per case ( P < .001) and an additional cost on the health system of $20,953.00 ± $186.3 per case ( P < .001). Conclusions SSI is associated with a significant mortality risk and burden on the health system. More than half of SSI cases were identified on readmission.