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Background: Mesh salvage using negative pressure wound therapy (NPWT) in cases of mesh infection following hernia repair has emerged as an alternative to early mesh removal. However, the factors related to the success or failure of mesh salvage with NPWT remain unclear. Methods: This retrospective cohort study included 61 patients with mesh infections after hernia repair treated with NPWT between 2018 and 2024. We analyzed demographic, clinical, and surgical variables, as well as the bacterial spectrum and antimicrobial susceptibility. A binary logistic regression model was used to identify factors associated with NPWT failure, defined as the need for mesh removal. Results: Mesh salvage was successful in 80.3% of cases. Active smoking was significantly associated with NPWT failure (OR = 7.82, CI 95% 1.05–64.8; p = 0.044). Other factors, such as age, body mass index, Charlson comorbidity index, mesh type, and mesh position, were not significantly related to failure. Most infections were caused by Staphylococcus aureus (24.6%) and Escherichia coli (22.9%). Conclusions: NPWT is an effective method for salvaging infected meshes, with a high success rate. Active smoking was identified as a risk factor for NPWT failure, highlighting the need for early identification of patients who may benefit from alternative approaches. Further studies are required to develop predictive models for NPWT success in mesh salvage. [ABSTRACT FROM AUTHOR]