Background and purpose - Clindamycin has not been compared with other antibiotics for prophylaxis in arthroplasty. Since 2009, the Swedish Knee Arthroplasty Register (SKAR) has been collecting information on the prophylactic antibiotic regime used at every individual operation. In Sweden, when there is allergy to penicillin, clindamycin has been the recommended alternative. We examined whether there were differences in the rate of revision due to infection depending on which antibiotic was used as systemic prophylaxis. Patients and methods - Patients who had a total knee arthroplasty (TKA) performed due to osteoarthritis (OA) during the years 2009-2015 were included in the study. Information on which antibiotic was used was available for 80,018 operations (55,530 patients). Survival statistics were used to calculate the rate of revision due to infection until the end of 2015, comparing the group of patients who received cloxacillin with those who received clindamycin as systemic prophylaxis. Results - Cloxacillin was used in 90% of the cases, clindamycin in 7%, and cephalosporins in 2%. The risk of being revised due to infection was higher when clindamycin was used than when cloxacillin was used (RR =1.5, 95% CI: 1.2-2.0; p = 0.001). There was no significant difference in the revision rate for other causes (p = 0.2). Interpretation - We advise that patients reporting allergic reaction to penicillin should have their allergic history explored. In the absence of a clear history of type-I allergic reaction (e.g. urticaria, anaphylaxis, or bronchospasm), we suggest the use of a third-generation cephalosporin instead of clindamycin as perioperative prophylaxis when undergoing a TKR. No recommendation can be given regarding patients with type-1 allergy.