The disease caused by permanent synthetic fillers (EIRSP) arises after the injection of non-biodegradable and non-biocompatible materials, such as silicone, methyl methacrylate, and mineral oils, into the body for aesthetic purposes. These materials can trigger both local and systemic immunological reactions, resulting in a series of complications. The main pathophysiological mechanism is a hypersensitivity reaction, which can cause damage to the body’s tissues and organs. These reactions are classified into four main types: type I, II, III, and IV hypersensitivity. Type IV hypersensitivity, with the formation of one or more granulomas, is responsible for the pathophysiology related to the application of permanent filler substances. Persistent inflammation can lead to significant fibrosis in the subcutaneous adipose tissue, changing the architecture of the area and causing deformity in many patients. It is crucial that healthcare professionals are aware of these risks when considering aesthetic procedures involving permanent synthetic fillers.