Purpose <p>Determine if there is a difference in post-operative infection rates in patients undergoing sialendoscopy who received pre-, post-operative, both pre and post, or no antibiotics.</p> Methods <p>Retrospective chart review of patients who underwent sialendoscopy with a single surgeon from 2020 to 2023 at a tertiary care center. Demographic, preoperative, intraoperative, and postoperative information was collected from each patient. Operative information collected included salivary glands explored, operative findings, and conversion to hybrid/open procedure. Statistical analysis included chi-squared test and descriptive statistics.</p> Results <p>164 sialendoscopies were included. 28.7% (<i>n</i> = 47) of procedures were converted to hybrid sialendoscopy. 26.8% (<i>n</i> = 44) received both pre- and postoperative antibiotics, 24.2% (<i>n</i> = 39) received only preoperative antibiotics, 10.6% (<i>n</i> = 17) only received postoperative antibiotics, and 39% (<i>n</i> = 64) did not receive any antibiotics. Overall, 2.6% (<i>n</i> = 3) of patients developed postoperative infections, 1 patient with acute sialadenitis, and 2 with infected sialoceles. 2 patients with postoperative infections received antibiotics (pre, post, or both). The third patient did not receive any antibiotics. There was no significant difference in infection rate between the 4 groups (<i>p</i> = 0.23).</p> Conclusions <p>Antibiotic administration in peri-operative period did not reduce infection rates in patients compared to those who did not receive any antibiotics. Infection rates did not differ if the sialendoscopy was converted to hybrid/open procedure. Based on this data, antibiotic usage for diagnostic sialendoscopy procedures may not be necessary, but needs to be studied in a prospective, clinical trial.</p>