Background/objective National guidelines do not recommend the routine use of antimicrobial prophylaxis in patients with solid tumors, yet prophylactic agents are still sometimes prescribed for head and neck cancer patients. The purpose of this study is to determine the effect of prophylactic antimicrobials on the incidence of infection in patients undergoing chemoradiation for head and neck cancer. Methods Between 2013 and 2016, patients receiving chemoradiation for head and neck cancer at three outpatient oncology clinics were identified by retrospective review. Cohorts were based on administration or absence of prophylactic antimicrobials. The primary outcome of this study was incidence of infection. Secondary outcomes included incidence of hospitalization and length of hospital stay. Results Seventy-seven patients were analyzed, 47% (n = 36) were not prescribed antimicrobial prophylaxis and 53% (n = 41) were prescribed prophylaxis. Infection occurred in 31 patients in the no prophylaxis cohort and in 34 patients in the prophylaxis cohort (86.1% vs. 82.9%, p = 0.945). Twenty patients in the no prophylaxis cohort were hospitalized versus 16 patients in the prophylaxis cohort ( p = 0.222). The average length of hospital stay was 6 days in the no prophylaxis cohort and 10.6 days in the prophylaxis cohort ( p = 0.007). Conclusion The use of antimicrobial prophylaxis did not significantly impact the incidence of infection when compared to patients who were not prescribed prophylaxis. There was no difference in the incidence of hospitalization, however, the patients in the prescribed prophylactic group had longer length of hospital stay.