Background: Late inflammatory reactions (LIRs) are the most challenging complications after filler use. The immune system plays a prominent role in its etiology, albeit to an unknown extent. Bacterial contamination in situ has been hypothesized to be causative for LIRs. How this relates to the immunological processes involved is unknown. This article aims to provide an overview of immunological and bacterial factors involved in development of LIRs. Methods: We undertook a systematic literature review focused on immunological factors and microbiota in relation to LIRs after filler use. This systematic review was performed in accordance with the PRISMA guidelines. PubMed, EMBASE and the Cochrane databases were searched from inception up to August 2019. Included studies were assessed for the following variables: subject characteristics, number of patients, primary indication for filler injection, implant type/amount and injection site, type of complication, follow-up or injection duration, study methods, type of antibiotics or medical therapies and outcomes related to microbiota and immunological factors. Results: Data on immunological factors and bacterial contamination were retrieved from 21 included studies. Notably, the presence of histocytes, giant cells and Staphylococcus epidermidis within biopsies were often associated with LIRs. Conclusion: This review provides a clear overview of the immunological factors associated with LIRs and provides a hypothetical immunological model for development of the disease. Furthermore, an overview of bacterial contamination and associations with LIRs has been provided. Follow-up research may result in clinical recommendations to prevent LIRs. Level of Evidence III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors-www.springer.com/00266.