Background: A randomized phase II/III trial of JCOG1008 demonstrated that chemoradiotherapy (CRT) with weekly cisplatin at 40 mg/m² (Weekly arm) was noninferior to 3-weekly cisplatin at 100 mg/m² (3-weekly arm) in terms of overall survival (OS) for postoperative high-risk head and neck cancer (hazard ratio [HR], 0.69 [99.1% CI, 0.37 to 1.27 < 1.32]; J Clin Oncol 2022; 40: 1980-90). Acute kidney injury (AKI) is a major dose-limiting toxicity of cisplatin. Here, we investigated the impact of AKI on OS in patients treated with CRT in JCOG1008. Methods: A total of 251 patients who were treated with CRT in JCOG1008 were analyzed. AKI was defined as an increase in serum creatinine of ≥0.3 mg/dL or a 1.5-fold or more increase from baseline (≥stage I) within 30 days after completion of CRT, based on the AKI Network classification/staging system. OS in the two arms was compared by the development of AKI using the log-rank test. Results: The total incidence of AKI in the weekly arm was lower than that in the 3-weekly arm (38 of 122 [31.1%] vs. 56 of 129 [43.4%]). The incidence of stage II/III AKI was also lower in the weekly arm (8 of 122 [6.6%] vs. 19 of 129 [14.7%]). Total cisplatin dose was similar in patients who did and did not develop AKI in the weekly arm, but was lower in patients who developed AKI in the 3-weekly arm (Table). Moreover, no difference in OS was observed between patients who did and did not develop AKI in the weekly arm (HR, 1.06 [95% CI, 0.53 to 2.10]), whereas patients who developed AKI in the 3-weekly arm had poorer OS than those who did not (HR, 1.83 [95% CI, 1.04 to 3.21]). Conclusions: In this supplementary analysis of JCOG1008, development of AKI impacted OS in the 3-weekly arm, but not in the weekly arm. Consistent exposure to cisplatin through weekly fractionated administration appears of greater clinical significance than cumulative dose, providing maintenance of treatment intensity and better kidney safety, and likely also improving outcomes. Clinical trial information: jRCTs031180135.