Background Endobronchial ultrasound-guided transbronchial biopsy (EBUS-TBB) helps facilitate the diagnosis of peripheral lung lesions. However, the prevention of infectious complications after EBUS-TBB has not been well established. Therefore, we analyzed short term oral antibiotics effects on the prevention of infectious complications. Methods We retrospectively analyzed 484 patients from the Radial EBUS Registry. Patients who underwent EBUS-TBB from March 2018 to March 2019 did not receive prophylactic antibiotics (“no prophylactic” group, n = 233), while patients who underwent EBUS-TBB from April 2019 to March 2020 did receive prophylactics (oral amoxicillin/clavulanate for 3 days; “prophylactic” group, n = 251). Multivariable logistic regression was used to identify independent factors for infectious complications. Results The median age of the study population was 66 years (IQR: 59-74 years), and 58.9% were male. Slightly over half of the patients (54.4%) were previous or current smokers. In 13% (n = 63) of patients, the procedure was performed using a guide sheath. Infectious complications occurred in 12 (5.2%) and 2 (0.8%) cases in the no prophylactic and prophylactic groups, respectively. In multivariable analysis, infectious complication was significantly related with cavitation (adjusted odds ratio [aOR], 9.065; 95% confidence interval [CI], 2.229-36.861; p = 0.002), low-density attenuation (LDA) of the lesion (aOR, 14.791; 95% CI, 3.969-55.114; p < 0.001), and combined obstructive pneumonic consolidation (aOR, 11.663; 95% CI, 1.259-108.030; p = 0.031), but prophylactic antibiotics was not a statistically significant factor (aOR, 0.251; 95% CI, 0.048-1.309; p = 0.101). In subgroup analysis, infectious complication occurred less when prophylactic antibiotics were used in patients with at least one risk factors (22.4% vs. 0%, p = 0.005). Conclusions Prophylactic antibiotics helped reduce the incidence of infectious complications after EBUS-TBB, especially patients with risk factors, such as cavitation, LDA in the lesion, and combined obstructive pneumonic consolidation.