Head and neck cancer patients undergoing chemoradiation experience considerable toxicities including acute kidney injury (AKI). However, it remains unclear what factors predispose patients to renal toxicity during treatment. Here, we assessed the predictors and outcomes of patients experiencing AKI during chemoradiation. We carried out a retrospective cohort study to assess the maximum changes in serum creatinine (Cr) in 173 patients with stage III-IV head and neck cancer treated with chemoradiation between 1999 and 2012. We defined AKI as Cr increases 26.5 µmol/l or more over the pretreatment baseline. AKI was associated with angiotensin-converting enzyme inhibitor (ACEI) use (33.0 vs. 11.0%; P=0.0004), but no other medications or comorbidities. On multivariate analysis, ACEI use, weight loss 10% or more of body weight, and performance status 70 or more predicted for Cr increments 26.5 µmol/l or more, whereas only ACEI use predicted for Cr increments of 44.2 µmol/l or greater. Furthermore, on multivariate analysis, AKI predicted for more interventions during radiotherapy including intravenous fluid use (P=0.0005) and hospitalizations (P=0.007), as well as long-term renal dysfunction (P<0.0001). Renal toxicity was not associated with worse locoregional control, progression-free survival, or overall survival. Renal toxicity during chemoradiation was associated with ACEI use alone or coupled with weight loss 10% or more of body weight during therapy. Our results suggest that actively managing ACEI use and intravascular volume status during chemoradiation may avoid AKI, minimize subsequent interventions, and reduce the risk for long-term renal dysfunction.