BACKGROUND Periprosthetic joint infection (PJI) is the most serious and feared complication in total knee arthroplasty (TKA) and can have catastrophic consequences. The number of total knee arthroplasties is increasing, so infections could also be greater in the future. The aim of this study is to identify the most relevant risk factors associated with infection after a total knee arthroplasty. METHODS This is a case-control study of patients who underwent total knee arthroplasty at the University Hospital of Salamanca. We included 66 TKA PJI patients and 66 control TKA patients. Demographic and clinical variables were collected. A descriptive and inferential analysis was performed by logistic regression and attributable risk fraction assessed. RESULTS Prolonged operative time (> 90') and tourniquet time (> 60') were the most relevant risk factors described (OR 40.77, AFE 0.97, p > 0.001 and OR 37.14, AFE 0.97, p < 0.001, respectively). The use of non-antibiotic-laded cement (OR 3.62), obesity (BMI > 30, OR 8.86), diabetes (OR 2.33), high ASA grade (III-IV, OR 15.30), and blood transfusion requirement (OR 4.60) were also statistically significant risk factors for TKA PJI. CONCLUSIONS Our study provides evidence concerning that operative time, tourniquet time, cement type, diabetes, obesity, ASA grade, and blood transfusion requirement as independently associated risk factors for TKA PJI. Modifiable risk factors were specifically relevant, so we should be able to reduce the infection rate.