Objectives <p>Peri-implant diseases are characterized by complex host-microbe interactions. This study aimed to investigate the levels of pro-apoptotic Bcl-2 family proteins and their relationship with <i>Porphyromonas gingivalis</i>-gingipain and <i>Treponema denticola</i>-dentilisin in peri-implant tissues.</p> Material and methods <p>Tissue samples were collected from 72 participants: healthy controls (n = 24), peri-implant mucositis (n = 23), and peri-implantitis (n = 25). Levels of pro-apoptotic proteins (Bax, Bad, Bim, Smac, and Lamin B) quantified via multiplex immunoassays, and proteases were analyzed using western blotting and normalized to total protein content. Regression models adjusted for age and clinical parameters assessed associations between microbial protease levels and apoptotic proteins.</p> Results <p>Pro-apoptotic protein levels were significantly lower in diseased sites compared to healthy controls (<i>p</i> &lt; 0.001). While absolute protease levels did not differ significantly between groups (<i>p</i> &gt; 0.05), multivariate regression models, adjusted for clinical parameters, revealed significant associations between gingipain/dentilisin and Bax/Bad levels (<i>p</i> &lt; 0.05).</p> Conclusions <p>The downregulation of pro-apoptotic proteins suggests a suppressed apoptotic response in peri-implant lesions, potentially contributing to disease persistence. The preliminary associations between bacterial proteases and apoptotic markers, independent of clinical severity, highlights these virulence factors as potential modulators of tissue homeostasis and candidates for future diagnostic and therapeutic targets.</p> Clinical relevance <p>Bacterial proteases show modest associations with host apoptotic pathways in peri-implant diseases. A better understanding of these relationships may potentially help develop new preventive and therapeutic strategies in the future.</p>