Simple Summary Chronic kidney disease (CKD) is a major cause of morbidity and mortality in cats. Despite the increasing worldwide interest in feline CKD, the specific role of systemic inflammation in these patients remains poorly defined. The aim of the present prospective study was to assess serum amyloid A (SAA) and erythrocyte sedimentation rate (ESR) levels as markers of inflammation in cats diagnosed with CKD at IRIS stages 2-4. The results indicate a systemic inflammatory state associated with feline CKD, as both markers showed significantly higher levels in affected animals than in healthy ones. Compared to SAA, the rise in ESR appears to be more closely linked to advanced stages of the disease and could, therefore, correlate with the uremic condition.Abstract This prospective study aimed to evaluate inflammatory status in cats affected by chronic kidney disease (CKD) at IRIS stages 2-4, using serum amyloid A (SAA) and the erythrocyte sedimentation rate (ESR) as inflammatory markers. Thirty-two cats with CKD and ten clinically healthy cats (i.e., control group) were enrolled. The recording of signalment data, complete physical examinations, and abdominal ultrasonography were performed for each animal. Additionally, ESR levels, complete blood count, clinical chemistry (including SAA determination), serum protein electrophoresis, and complete urinalysis were executed. This study's results showed that mean ESR and SAA concentrations in cats with CKD were statistically higher compared to those of the control group (p = 0.0005 and p = 0.007, respectively). The SAA concentration was significantly increased at IRIS stages 2, 3, and 4 compared to the control group. Meanwhile, the ESR was significantly higher in cats at IRIS stages 3 and 4 (p = 0.0003 and p = 0.0007, respectively), but not at IRIS stage 2, compared to the control group. These results provide evidence that feline CKD is associated with a systemic inflammatory status. Moreover, the rise in ESR appears to be more linked to advanced stages of the disease and could, therefore, correlate with the uremic condition.