The objective of this study was to identify, through multivariate analyses, the configuration of factors that most closely impact the development of pharyngocutaneous fistula (PCF). Incidence and treatment of PCF was also revisited. A retrospective longitudinal study of 218 patients who have undergone total laryngectomy (TL) was conducted in a tertiary academic referral center. There were 47 patients (21.6%) developing PCF within 1 month after surgery (median 14 days, range 2-26 days). Non-surgical closure of the PCF was achieved in 36 patients (76.6%) within a median of 16.5 days (range 8-27 days). Eleven patients (23.4%) required a surgical closure of the PCF. In nine patients the surgical approach consisted in resuturing of the pharyngeal mucosa. Major surgery with the use of flaps (pectoralis major myocutaneous flap and free forearm flap) was required in two patients. Multivariate analysis revealed that diabetes mellitus (odd ratio 23.41 [95% CI 8.46-64.78]), preoperative hypoalbuminemia (odd ratio 9.42 [95% CI 3.60-24.61]), chronic pulmonary diseases (odd ratio 6.64 [95% CI 1.97-22.56]) and chronic hepatopathy (odd ratio 3.26 [95% CI 1.19-9.96]) were independent predictors for PCF formation. PCF results in prolonged hospitalization with increased medical costs, delay of adjuvant postoperative therapy and potentially life-threatening complications such as carotid rupture. In order to reduce the risk of PCF and avoid a delayed TL, optimization of comorbidities and correction of nutritional deficiencies with enteral or parenteral nutritional supplements should be achieved as early as possible.