To determine the association between the use of preoperative antibiotics and the risk of postoperative infection after simple knee arthroscopy. The electronic medical records of a large integrated health care organization were used to identify patients who underwent simple knee arthroscopy between 2007 and 2012. Patient demographics, potential infection risk factors, and antibiotic administration data were extracted. Simple knee arthroscopy included debridement, meniscectomy, meniscus repair, synovectomy, microfracture, and lateral release. Complex knee arthroscopy, septic knees, and cases involving fractures were excluded. Deep infection was defined as a positive synovial fluid culture or signs and symptoms of infection and gross pus in the knee. Superficial infection was defined as clinical signs of infection localized to a portal site and treatment with an antibiotic. Of 40,810 simple knee arthroscopies, 32,836 (80.5%) received preoperative antibiotics and 7,974 (19.5%) did not. There were 25 deep infections in the antibiotic group (0.08%) and 11 in the no-antibiotics group (0.14%) (risk ratio = 0.55, 95% confidence interval: 0.27 to 1.12, P = .10). There were 134 superficial infections in the antibiotic group (0.41%) and 32 in the no-antibiotics group (0.40%) (risk ratio = 1.01, 95% confidence interval: 0.29 to 1.49, P = .93). In our large sample of patients who underwent simple knee arthroscopy, there was no association between preoperative antibiotic use and postoperative deep or superficial infection rates at the 95% confidence level (P = .05). There was an association between preoperative antibiotic use and a decreased deep infection rate at the P = .10 level. Level IV, case series.