Background.Surgical-site infection (SSI) is the most common early infectious complication after pancreas transplantation (PT). Although SSI has been shown to worsen outcomes, little data exist to guide optimal choices in perioperative prophylaxis.Methods.We performed a retrospective cohort study of PT recipients from 2010–2020 to examine the effect of perioperative antibiotic prophylaxis withEnterococcuscoverage.Enterococcuscoverage included antibiotics that would be active for penicillin-susceptibleEnterococcusisolates. The primary outcome was SSI within 30 d of transplantation, and secondary outcomes wereClostridioides difficileinfection (CDI) and a composite of pancreas allograft failure or death. Outcomes were analyzed by multivariable Cox regression.Results.Of 477 PT recipients, 217 (45.5%) received perioperative prophylaxis withEnterococcuscoverage. Eighty-seven recipients (18.2%) developed an SSI after a median of 15 d from transplantation. In multivariable Cox regression analysis, perioperativeEnterococcusprophylaxis was associated with reduced risk of SSI (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.35-0.96;P= 0.034). Anastomotic leak was also significantly associated with elevated risk of SSI (HR 13.95; 95% CI, 8.72-22.32;P< 0.001). Overall, 90-d CDI was 7.4%, with no difference between prophylaxis groups (P= 0.680). SSI was associated with pancreas allograft failure or death, even after adjusting for clinical factors (HR 1.94; 95% CI, 1.16-3.23;P= 0.011).Conclusions.Perioperative prophylaxis withEnterococcuscoverage was associated with reduced risk of 30-d SSI but did not seem to influence risk of 90-d CDI after PT. This difference may be because of the use of beta-lactam/beta-lactamase inhibitor combinations, which provide better activity against enteric organisms such asEnterococcusand anaerobes compared with cephalosporin. Risk of SSI was also related to anastomotic leak from surgery, and SSI itself was associated with subsequent risk of a poor outcome. Measures to mitigate or prevent early complications are warranted.