Background <p>Many studies have examined the relationship between biofilm layers and capsular contracture, but this condition, which is usually polymicrobial, could not be evaluated in isolation from other reasons. In this study, we aimed to investigate which of the bacteria involved in the etiology of capsular contracture and to compare the cytological differences that occur after the host’s immune response around silicone materials contaminated with different bacteria.</p> Methods <p>Forty-four rats were divided into four groups. A sterile implant was placed on the backs of female rats. (Group 1—control) An implant contaminated with a <i>Staphylococcus epidermidis</i> non-biofilm-forming strain was placed on the backs of female rats. (Group 2) An implant contaminated with a <i>Staphylococcus epidermidis</i> biofilm-forming strain was placed on the backs of female rats. (Group 3) An implant contaminated with a <i>Cutibacterium acnes</i> was placed on the backs of female rats. (Group 4).</p> Results <p>A statistically significant difference was found between the groups in terms of macrophage–histiocyte counts (<i>p </i>= 0.002). When the groups were compared pairwise, there was a significant difference between Group 1 and Group 3 (<i>p</i> = 0.001) and between Group 2 and Group 3 (p=0.045). Capsule thicknesses were found to be 85.4±30.3 µm, 134.4±36.1 µm, 197.5±67.5 µm, and 182.8±46.6 µm for Group 1, Group 2, Group 3, and Group 4, respectively. A statistically significant difference was determined between the groups in terms of capsule thicknesses (<i>p</i> &lt; 0.001). When the groups were compared pairwise, there was a significant difference between Group 1 and Group 3 (<i>p</i> &lt; 0.001) and between Group 1 and Group 4 (<i>p</i> &lt; 0.001).</p> Conclusions <p>To prevent the formation of a capsule around the implant material, which can result in contracture, studies should be conducted on implant materials with surfaces that prevent the adhesion of <i>Staphylococcus epidermidis</i> and <i>Cutibacterium acnes</i> pathogens, which can form a biofilm layer, and on implants that can release antimicrobials with bactericidal properties against these pathogens and/or immunomodulatory drugs that locally suppress macrophage activation around the prosthesis for long-term periods.</p> No Level Assigned <p>This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors <a href="http://www.springer.com/00266">www.springer.com/00266</a>.</p>