Background: This study aimed to investigate whether periprosthetic joint infection (PJI) can be predicted by the C-reactive protein-to-lymphocyte ratio (CLR), whether this ratio increases the accuracy of PJI diagnosis, and whether it is more sensitive than other blood values and ratios. Methods: The patients were divided into two groups: the septic revision (SR) group and the aseptic revision (AR) group. In cases of septic revision, the diagnosis of PJI was made based on the criteria proposed by the European Bone and Joint Infection Society (EBJIS). The groups were compared in terms of age, sex, body mass index, comorbidity, and preoperative laboratory results. The sensitivity, specificity, and diagnostic performance of the values and ratios were analyzed and compared. Results: The receiver operating characteristic (ROC) analysis for the CLR gave a diagnostic value of 15.52, which provided a sensitivity of 91.1% and a specificity of 64.2% for PJI. The CLR gave lower specificity and higher sensitivity compared to the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. The ROC analysis showed that the CLR had a similar area under the curve (AUC) with the ESR and CRP (0.808). The CLR had a higher specificity than other ratios (platelet volume ratio, neutrophil-tolymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio) and a higher value of the AUC. In the multivariate analysis, the CLR (hazard ratio, 1.088; 95% confidence interval, 1.063–1.113; p < 0.001) was found to be a significant risk factor. As CLR increased by one unit, the risk of PJI increased by 1.088 times, and it was statistically significant (p < 0.001). Conclusions The findings of this study suggest that CLR can serve as a valuable screening tool for diagnosing PJI. CLR demonstrated higher sensitivity in predicting PJI compared to ESR and CRP, and it exhibited greater specificity than other infection markers.