Background <p>Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth, kidney enlargement, and decline in renal function. Increasing evidence suggests that inflammatory processes may contribute to disease progression. This study aimed to evaluate the association between tolvaptan use, systemic inflammatory markers, and total kidney volume (TKV) progression in patients with ADPKD.</p> Methods <p>This retrospective study included 67 patients with ADPKD, including 40 receiving tolvaptan and 27 untreated controls. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), estimated glomerular filtration rate (eGFR), and TKV were evaluated at baseline and after 24 months. Longitudinal changes were assessed using Wilcoxon signed-rank tests and linear mixed-effects models.</p> Results <p>Patients receiving tolvaptan were younger and had higher baseline TKV values than untreated patients. During follow-up, NLR, PLR, and SII decreased in the tolvaptan group, whereas these markers increased in untreated patients. eGFR declined in both groups but appeared less pronounced in patients receiving tolvaptan. TKV increased in both groups; however, the percentage increase in TKV was lower among patients receiving tolvaptan. Significant time × treatment interactions were observed for NLR, PLR, SII, and TKV. In the non-tolvaptan group, NLR at 24 months showed a significant positive association with TKV.</p> Conclusions <p>Tolvaptan use was associated with differences in longitudinal changes in systemic inflammatory markers and kidney volume progression in ADPKD. Further prospective studies are needed to clarify the clinical relevance of these associations.</p>