Background: Periprosthetic joint infections (PJIs) are associated with altered coagulation dynamics; therefore, coagulation laboratory studies could be valuable for diagnosing PJI. This study aimed to evaluate the diagnostic role of Rotational Thromboelastometry (ROTEM) in detecting PJIs caused by low-virulence pathogens. Methods: A retrospective study was conducted, enrolling 78 patients who underwent exchange arthroplasty due to PJI due to high-virulence pathogens (Group A, n = 16), low-virulence pathogens (Group B, n = 20), or due to aseptic loosening (Group C, n = 20). Preoperative laboratory findings were compared among the three groups. Results: Several ROTEM parameters differed in patients with PJIs caused by low-virulence pathogens, indicating a link between these infections and hypercoagulability. The development of low-virulence PJIs was associated with a higher maximum clot firmness (MCF) (Odds Ratio, 1.12; 95% Confidence Interval, 1.04–1.21; p = 0.001). Additionally, EXTEM MCF was found to have the highest diagnostic accuracy for these infections (Area Under the Curve, 0.841; sensitivity 90.0%; specificity 90.4%), surpassing that of C-reactive protein and the Erythrocyte Sedimentation Rate (p = 0.006 and p = 0.019, respectively). Conclusions: Our findings suggest that ROTEM analysis is a promising method for detecting the altered hemostatic dynamics associated with PJI caused by low-virulence pathogens.