Background: The determination of cytokines in the postoperative drainage (POD) fluid could be a method for early detection of the development of a pharyngocutaneous fistula (PCF). Materials and methods: We conducted a prospective two‐center study involving 28 patients. PODs were collected on Day 1 (D1) and Day 2 (D2) postoperatively for determination of a cytokine panel and cytobacteriological examination. Results: Eleven (39%) patients presented with PCF on average 13 ± 5.5 days after surgery. Patients with PCF had higher IL‐10 (121 vs. 40.3, p = 0.04, effect size (ES) = 0.98 [0.16, 1.79]) and TNFα level (21.2 vs. 2.2, p = 0.02, ES = 0.83 [0.03, 1.63]) on D2. An IL‐10 threshold of 72 pg/mL on D2 was diagnostic of the occurrence of PCF with a sensibility of 70%, specificity of 88%. Conclusion: The determination of cytokines in POD fluid on D2 is a reliable tool for predicting the development of a PCF after total laryngectomy.