Background: Despite the recent introduction of the CMS metric, OP-35, which tracks 30-day inpatient admissions and ED visits after outpatient chemotherapy administration, the risk factors driving acute care utilization (ACU) in the head and neck cancer treatment setting are not yet well understood. Further characterization of these risk factors could allow for improved care quality and reduce preventable inpatient and ED admissions. Methods: This was a retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked cancer registry-claims database. The study cohort consisted of patients aged 66 years or older diagnosed with head and neck cancer between 2004-2015 who received outpatient chemotherapy within the first two years after diagnosis. Multivariable logistic regression modeling was utilized to characterize the risk factors associated with an inpatient or ED admission within 30 days after receiving chemotherapy. Results: Of the 2,236 eligible patients, 735 (32.9%) had at least one inpatient or ED admission within 30 days of receiving outpatient chemotherapy. On multivariable analysis, cancer of the oral cavity [odds ratio (OR) 1.43; 95% confidence interval (CI) 1.04-1.96] and oropharynx/hypopharynx [OR 1.34; 95% CI 1.06-1.70] were associated with an increased odds of ACU. Other factors associated with ACU included NCI comorbidity index [OR 1.10; 95% CI 1.03-1.18], prior ACU [OR 1.06; 95% CI 1.02-1.09], second cycle of chemotherapy relative to the first cycle [OR 0.38, 95% CI 0.29-0.50], and third or greater cycle of chemotherapy [OR 0.17; 95% CI 0.13-0.21]. Certain chemotherapeutic agents also modified risk: use of an angiogenesis inhibitor [OR 0.18; 95% CI 0.06-0.45], alkylating agent [OR 1.24; 95% 1.01-1.53], plant alkaloid [OR 1.63; 95% CI 1.25-2.10], or antimetabolite [OR 2.69; 95% CI 1.78-4.09]. The most common admission diagnosis was pain (n = 243; 33.1%) followed by dehydration (n = 167; 22.7%). Conclusions: Multiple clinical variables modify risk of acute care utilization after outpatient chemotherapy in the head and neck cancer setting, providing several potential avenues of intervention for providers.