PURPOSE: The diagnostic criteria of prosthetic joint infection (PJI) recommended by the most commonly used diagnostic algorithms can be obscured or distorted by other inflammatory processes or aseptic pathology. Furthermore, the most reliable diagnostic criteria are garnered during revision surgery. A robust, reliable addition to the preoperative diagnostic cascade is warranted. Calprotectin has been shown to be an excellent diagnostic marker for PJI. In this study, we aimed to evaluate a lateral flow test (LFT) in the challenging patient cohort of a national referral centre for revision arthroplasty. METHODS: Beginning in March 2019, we prospectively included patients scheduled for arthroplasty exchange of a total hip (THA) or knee arthroplasty (TKA). Synovial fluid samples were collected intra-operatively. We used the International Consensus Meeting of 2018 (ICM) score as the gold standard. We then compared the pre-operative ICM score with the LFT result to calculate its diagnostic accuracy as a standalone pre-operative marker and in combination with the ICM score as part of an expanded diagnostic workup. RESULTS: A total of 137 patients with a mean age of 67 (± 13) years with 53 THA and 84 TKA were included. Ninety-nine patients (72.8%) were not infected, 34 (25.0) were infected, and four (2.9%) had an inconclusive final score and could not be classified after surgery. The calprotectin LFT had a sensitivity (95% confidence interval) of 0.94 (0.80-0.99) and a specificity of 0.87 (0.79-0.93). The area under the receiver operating characteristic curve (AUC) for the calprotectin LFT was 0.94 (0.89-0.99). In nine cases with an inconclusive pre-operative ICM score, the calprotectin LFT would have led to the correct diagnosis of PJI. CONCLUSIONS: The synovial fluid calprotectin LFT shows excellent diagnostic metrics both as a rule-in and a rule-out test, even in a challenging patient cohort with cases of severe osteolysis, wear disease, numerous preceding surgeries, and poor soft tissue conditions, which can impair the common diagnostic criteria. As it is available pre-operatively, this test might prove to be a very useful addition to the diagnostic algorithm.