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Despite the prolongation of hospitalization, increase in morbidity, mortality and cost of care associated with both surgical site infections (SSIs) and antibiotic resistance, there are limited data on SSIs and antibiotic resistance to guide prevention strategies in Sierra Leone. This study assessed the burden of SSIs and related antibiotic resistance in the 34 Military Hospital (MH) and Makeni Government Hospital (MGH) located in two geographic regions of Sierra Leone using a prospective study design to collect data from adults aged 18 years or older. Of the 417 patients, 233 (55.9%) were enrolled in MGH. Most were women 294 (70.5%). The incidence rate of SSI was 5.5 per 1000 patient-days, and the cumulative incidence of SSI was 8.2%. Common bacteria isolated in MH were Escherichia coli (6,33.3%) and Pseudomonas aeruginosa (3,16.7%) and in MGH were P. aeruginosa (3,42.9%) and Proteus mirabilis (2,28.9%). Of the gram-negative bacteria, 40% were Extended-spectrum beta-lactamase-producing Enterobacteriaceae , 33% were Carbapenem-resistant P. aeruginosa and 10% were carbapenem-resistant Enterobacteriaceae . Although the incidence of SSIs in our study is lower than previously reported, the rate of antibiotic resistance reported in this study is high. Urgent action is needed to invest in the microbiology infrastructure to support SSI surveillance and prevention strategies., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.F. receives his salary from the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie (Grant No. 801076), through SSPH+ Global PhD Fellowship Programme in Public Health Sciences (GlobalP3HS). G.A.Y. reports salary support from the National Institutes of Health/AIDS Clinical Trials Group under Award Nos. 5UM1AI068636-15, 5UM1AI069501-09 and AI068636(150GYD212), and consultancy fees from Pfizer. All other authors do not have any conflict of interest., (© The Author(s), 2022.)