BACKGROUND: Antibiotics play a crucial role in preventing surgical site infections, yet adherence to Infectious Disease Society of America guidelines varies widely. This qualitative study aimed to explore factors influencing perioperative antibiotic administration and assess the potential impact of a clinical decision support tool on guideline adherence. METHODS: In this qualitative study, perioperative personnel with diverse roles (surgeons, anesthesiologists, certified nurse anesthetists, trainees, and pharmacists) were interviewed using a semistructured interview format from September 2023 through April 2024. Interviews were then analyzed for codes, which were assigned to concepts using the constant comparison method for assessment of factors that were described as barriers or facilitators of guideline adherence. RESULTS: After 3 piloting interviews, 9 sessions were conducted with a total of 17 participants: 7 attending anesthesiologists, 3 resident trainees, 2 perioperative pharmacists, 3 Certified Registered Nurse Anesthetists, and 2 attending surgeons. Key themes emerged: (1) limited familiarity with Infectious Disease Society of America antibiotic guidelines, (2) lack of standardization and optimization of antibiotic decision-making process, (3) challenges with managing β-lactam allergies, (4) difficulty optimizing vancomycin timing, and (5) perceived benefit of a clinical decision support tool in enhancing workflow and guideline adherence. CONCLUSIONS: Nonadherence to antibiotic guidelines in the perioperative setting often results from a lack of structured workflow. The interviews provide a foundation for developing a clinical decision support tool tailored to provider needs, aiming to improve user satisfaction and promote better adherence to perioperative antibiotic guidelines.