Background: Surgical site infection (SSI) in laryngeal cancer (LC) patients significantly increases morbidity and may postpone adjuvant therapy. Additionally, SSI can prolong hospitalization, thus representing a burden for the healthcare system. Most of the published studies refer to SSI after salvage laryngectomy. Methods: The present prospective cohort study aimed to clarify the incidence and factors associated with SSI in patients after primary open surgery for LC. Through regular hospital surveillance of patients who underwent primary partial or total laryngectomy, we gathered 24 putative factors and identified SSI from 2013 to 2022. Patients with SSI were compared with patients without SSI. Results: SSI was observed in 21 (6.6%) of 319 patients. ULRA showed that the occurrence of SSI was significantly associated with the American Society of Anesthesiologists (ASA) score, other postoperative healthcare-associated (HAI) infection, T classification, N classification, advanced clinical stage (III–IV), length of stay (LOS), duration of drainage, and the National Healthcare Safety Network (NHSN) risk index. Multivariate logistic regression analysis identified two independent factors associated with SSI occurring in these patients: duration of drainage (RR (relative risk) 1.593; 95% CI 1.159–2.189; p = 0.004) and LOS (RR: 1.074; 95% CI: 1.037–1.112; p < 0.001). Conclusions: Our study provided insight into the burden of SSI in LC patients, highlighting several priority areas and targets for quality improvement.