Objectives <p>The conducted longitudinal controlled clinical study aimed to determine the microbiological and clinical periodontal changes in patients with chronic kidney disease before and after kidney transplantation and its associated drug-induced immunosuppression.</p> Materials and methods <p>Baseline radiological, clinical, and microbiological evaluations of fifteen kidney recipients and donors were performed prior to kidney transplantation, with six weeks and six months follow-up assessments. Clinical evaluations included periodontal probing depth (PPD), bleeding on probing (BOP), and clinical attachment loss (CAL) for kidney donors and recipients. Microbiological analysis was performed on samples from the deepest periodontal pockets, analyzed by next-generation sequencing.</p> Results <p>In kidney recipients, there was a reduction for BOP six weeks post-transplant, followed by an increase at six months, along with an improvement in CAL scores and a reduction in the deepest probing depths. Alpha diversity decreased significantly (<i>p</i> = 0.0311), while beta diversity changed significantly, indicating substantial changes in the bacterial community structure (<i>p</i> = 0.001), with a notable decrease in <i>Aggregatibacter</i> and <i>Porphyromonas</i>, correlating with immunosuppressive therapy. In kidney donors, there were no significant changes in alpha and beta diversity but shifts in the relative abundance of certain bacterial genera were noted.</p> Conclusions <p>Immunosuppressive therapy after kidney transplantation effects periodontal health and microbiome composition. Kidney recipients showed initial improvements in periodontal health but did not maintain these changes long-term.</p> Clinical relevance <p>The findings highlight the importance of regular periodontal care in transplant patients and further longitudinal studies. The trial was registered in the German Clinical Trials Register (DRKS-ID: DRKS00031639) (05/04/2023).</p>