Silicone-based breast implants are commonly used, but there are concerns about their long-term safety. While implantation results in the formation of a periprosthetic tissue that isolates the implant from the rest of the host body, silicone can leak and reach surrounding tissues. We combined histological analysis and gene expression profiling (RNA sequencing) of samples from human patients with silicone breast implants with different fillers (silicone or serum), surface topographies and/or shell rupture, and performed systematic cross-comparisons. Our study shows that exposure to silicone gel filler, even in clinically asymptomatic cases, induces an immune response. This response includes the expression of markers associated with various autoimmune diseases. This study provides the first biological evidence of an association between silicone implants and autoimmune markers, highlighting the need for further research and stricter implant safety regulations. We suggest that implant design factors, such as filler type and surface texture, may influence the inflammatory response. Re-evaluation of existing clinical trials is warranted to investigate the association between implant characteristics and potential health risks.