Background: Cisplatin ( Cis) is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Little is known about the incidence of hearing loss when using different cisplatin schedules in patients receiving concomitant CRT. We, therefore, assessed prospectively the incidence of ototoxicity in patients receiving weekly or triweekly Cis concomitantly with radiation. Methods: Head and Neck Squamous Cell Cancer patients receiving definitive or adjuvant cisplatin-based CRT were included. Cisplatin was administered weekly (40 mg/m2 weekly, 7 cycles) or triweekly (100 mg/m2 every three weeks, 3 cycles). Radiation was administered to a total dose of 70 Gy as definitive treatment or 66 Gy as adjuvant treatment (2 Gy/fraction). Intensity-modulated radiation therapy was used in all cases. Pure-tone air-conduction audiometry was performed in all pts before starting and after completion of CRT. The primary endpoint of the analysis was Common Terminology Criteria for Adverse Event (CTCAE v4.0) hearing change ≥3 at the end of CRT. Results: A total of 96 pts (M:77/F:19) were included (oropharynx 56 pts, other 40). Age: 55y (26-78). 68 pts received weekly cis and 28 triweekly regimen. 58 pts received definitive treatment and 38 adjuvant treatment. Nine pts receiving weekly cis (13%) experience G3 ototoxicity vs 14 pts (50%) receiving triweekly cis (P < 0.001, OR = 6.4, 95% CI 2.1-20.7). Risk of ototoxicity was not associated with age, cis cumulative dose, sex, tumor primary site, or CRT modality (definitive vs. adjuvant). After adjusting for these factors in a multivariable model cis schedule remained significant (OR = 8.7, 95% CI 2.31-32.75, p = 0.001). With a minimum follow-up of three months, the complete response rate after treatment was 84% for weekly CRT and 86% for triweekly CRT. Conclusions: Triweekly Cis-based CRT increases the risk of irreversible severe ototoxicity. This risk should be discussed with patients that are candidates for cis-based CRT.