Background: Surgical site infections (SSIs) are among the most important determinants of morbidity after HBP surgery. Their frequency after HPB surgery is variable, from 1–2% after elective cholecystectomy to 25% after PD. Methods: A systematic review was performed to assess the role of antimicrobial prophylaxis (AP) in HPB elective surgery. Articles published between 2015 and 2021 were obtained; those before 2015 were not included because they antedate the WHO guidelines on SSI prevention. We conducted three different research methods for liver resection, elective cholecystectomy and pancreatic and biliary surgery regarding patients requiring preoperative biliary drainage. Results: Hepatic surgery, improvement in surgical technique and perioperative management lead to a very low SSI. One preoperative 2 g cefazolin dose may be adequate for surgical prophylaxis. From preoperative biliary drainage, we can derive that patients’ homeostasis rather than AP plays a paramount role in reducing postoperative morbidity. The time from biliary drainage could be an essential element in decision making for surgical prophylaxis. In the case of low-risk cholecystectomy, it is not easy to draw definitive conclusions about the effect of AP. Data from the literature are inconsistent, and some risk factors cannot be predicted before surgery. Conclusion: in our opinion, a strict preoperative cefazolin dose strategy can be reasonable in HBP surgery until a large-scale, multicentric RCT brings definitive conclusions.