Distinguishing periprosthetic crystalline arthropathy from periprosthetic joint infection (PJI) remains a diagnostic challenge as both symptom presentation and diagnostic tests overlap. Accurate differentiation is important as treatment plans vary significantly. We sought to systematically review all cases of total knee arthroplasty (TKA) periprosthetic crystalline arthropathy reported in the literature and summarize clinical, diagnostic, and operative findings in the context of guidelines for diagnosing PJI. The goal of this systematic review is to determine the amount of diagnostic overlap and to identify best practices for differentiating between these two diagnoses. MEDLINE and Google Scholar were searched to identify cases of crystalline arthropathy following TKA. Case reports were reviewed for patient characteristics, clinical symptoms, physical exam, laboratory results, and treatment outcomes. These findings were summarized across patients and dichotomized based on current thresholds for diagnosing PJI according to Musculoskeletal Infection Society criteria. Twenty-six articles were identified which included 42 cases of periprosthetic crystalline arthropathy (17 gout, 16 pseudogout, one both, and eight not specified). Of these cases, 25 presented over 1 year after their index arthroplasty and 15 had no prior history of crystalline arthropathy. Only six cases had a superimposed infection based on aspiration or intraoperative cultures. For cases without a culture-positive infection, several diagnostic tests overlap with PJI thresholds: 95% of patients had C-reactive protein greater than 1 mg/dL, 76% had an erythrocyte sedimentation rate greater than 30 mm/hour, 91% had a synovial white blood cell greater than 3,000 cells, and 76% had a synovial polymorphonuclear cells percent greater than 80%. Patients without co-infection were managed with non-steroidal anti-inflammatory drugs, colchicine, allopurinol, steroids, or a combination of these treatments and most had complete resolution of symptoms within 1 week. Commonly used markers of PJI fail to reliably distinguish periprosthetic crystalline arthropathy from infection. Though clinical judgement and consideration of the implications of delayed treatment for acute PJI remain paramount, in the setting of synovial crystals, surgeons may wish to consider this alternate etiology as the source of the patient's clinical symptoms.