PURPOSE: The widely used triple-antibiotics irrigation solution, comprising cefazolin, gentamycin, and povidone-iodine solution, has been employed for preventing infection and capsular contracture in implant-based breast reconstruction. However, potential overlapping in the coverage of such antimicrobial effects and the recent emergence of cefazolin-resistant gram-positive bacteria has prompted concerns regarding the efficacy of routine use of cefazolin in irrigation solutions. This study aims to evaluate clinical safety of omitting cefazolin from the traditional triple-antibiotic irrigation solution. METHODS: Patients who underwent immediate prepectoral direct-to-implant breast reconstruction between September 2020 and April 2022 were reviewed. They were divided into two groups: cases using the traditional triple-antibiotics for the former third and those using dual-antibiotics (omitting cefazolin) for the latter. Development of postoperative complications were compared by the type of irrigation solution and its independent associations with the adverse outcomes were evaluated. RESULTS: In total, 445 cases (126 using triple- and 319 using dual-regimen solution) were analyzed with a mean follow-up period of 12 months. The two groups had generally similar baseline characteristics. Overall complications developed in 126 cases (28.3%), including 12 (2.7%) of infection and 32 (7.2%) of capsular contracture. The complication profiles did not differ between the groups. Multivariable analyses exhibited that the type of irrigation solution was not associated with the development of overall and any kind of complication including infection and capsular contracture. CONCLUSION: Omission of cefazolin from the irrigation solution may not elevate the risks of infection and capsular contracture in prepectoral direct-to-implant reconstruction. Further long-term studies would be warranted. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .