Current diagnostic modalities are based almost exclusively on laboratory findings and the role of clinical presentation remains unknown. The purpose of this study was to examine the diagnostic value of clinical presentation in detecting periprosthetic joint infection (PJI). This study evaluated 279 patients undergoing revision surgery for failed total knee arthroplasty (TKA) between 2001-2016. Patients were classified as undergoing septic revisions based on major MSIS criteria. Aseptic revisions were defined as cases of single stage revision that did not have suspected PJI, fulfill MSIS criteria, or subsequently fail within one year of follow-up. Clinical presentation included pain, fever, presence of joint effusion or erythema, and reduced range of motion. Serum and synovial laboratory markers were also evaluated. The diagnostic value of each test was assessed and a Fagan's nomogram was constructed. A subset of MSIS-negative patients was used to demonstrate the value of various clinical presentations in detecting PJI. Post-test probability for infection was calculated taking into account clinical presentation together with serum and synovial markers. Our results show that fever and erythema are the most important signs for diagnosing PJI with a positive likelihood ratio (LR) of 10.78 and 8.08, respectively. Effusion had a LR of 2.42. Pain and reduced ROM were not as strongly correlated with PJI diagnosis; LR was 1.02 and 1.51. Of the 35 MSIS-negative patients treated for PJI, 33 had a post-test probability of infection greater than 90% when taking clinical presentation into account. Clinical presentation should be used to guide which future diagnostic tests should be ordered and in the interpretation of their results. Our results indicate that pain, fever, presence of joint effusion or erythema, and reduced range of motion should prompt further workup for infection. We propose a nomogram that may be used in interoperating their individual weight together with laboratory findings. Fever and erythema are highly specific findings in patients with PJI and future studies should assess whether they may be added as minor criteria to current definitions for infection.