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 has increased and will continue to increase so that the number of infections will 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 prosthesis in a Spanish population. Methods: This is a case-control study of patients who underwent total knee arthroplasty at the University Hospital of Salamanca during the period January 1 2010 until January 1, 2015. TKA PJI was detected in 66 patients. As controls, a similar number of patients from the same period who did not develop a periprosthetic infection were included. Demographic and clinical variables were collected. A descriptive and inferential analysis was performed. Results: Diabetes, ASA grade, obesity and the use or not of antibiotic loaded cement were statistically significant related to the appearance of the infection. For the variables of surgical time and ischemia time, this relationship disappeared when the logistic regression was made. Conclusions: Our study provides evidence that diabetes, cement type, ASA and BMI were independently associated with increased risk of PJI for TKA patients in a Spanish population. We think that modifiable risk factors were specifically relevant and for that reason we can reduce the infection rate.