OBJECTIVES:  In CheckMate 141 (NCT02105636), nivolumab was shown to have survival and health-related quality-of-life benefits versus IC of single-agent therapy (methotrexate, docetaxel, or cetuximab) in patients with platinum-refractory R/M SCCHN. Using data from CheckMate 141, we assessed the impact of treating platinum-refractory R/M SCCHN with nivolumab versus IC on HCRU and associated costs. METHODS:  Using non–protocol-specified hospitalization and medical visit data from CheckMate 141, the number of HCRU events and percentage of patients who experienced those events were compared between treatment arms from baseline through end of safety follow-up. Negative binomial regression adjusting for patient differences in length of study follow-up was used to examine differences in HCRU by treatment arm, with coefficients transformed to incidence rate ratios (IRRs). Using a US perspective, economic burden of HCRU was extrapolated by attaching unit costs from the Medical Expenditure Panel Survey to per-patient average numbers of events. Costs were calibrated to 2011 values (USD). RESULTS:  Nivolumab-treated patients had a 29% lower rate of hospitalization than those treated with IC (IRR=0.71 [95% confidence interval (CI): 0.50-0.99]; P=0.046). Rates for emergency department visits (IRR=0.72 [95% CI: 0.24-2.13]), hospital outpatient visits (IRR=0.87 [95% CI: 0.38-1.99]), and other visits (IRR=0.86 [95% CI: 0.39-1.91]) were qualitatively lower for nivolumab versus IC. Using the United States as a base case, average per-patient costs for nivolumab versus IC were lower for all forms of HCRU except physician office visits. The total per-patient HCRU cost for nivolumab ($21,779) was 13% lower than that for IC ($24,961). CONCLUSIONS:  In CheckMate 141, nivolumab-treated patients had a lower rate of hospitalization than IC-treated patients. Differences in rates of hospitalization and other events translated into substantial differences in estimated costs of care. The full economic implications of these differences should be interpreted carefully as not all potentially related costs were assessed.