AbstractMulti-drug resistant organisms (MDR-Os) are emerging as a significant cause of surgical site infections (SSI), but clinical outcomes and risk factors associated to MDR-Os-SSI have been poorly investigated in general surgery. Aims were to investigate risk factors, clinical outcomes and costs of care of multi-drug resistant organisms (MDR-Os-SSI) in general surgery. From January 2018 to December 2019, all the consecutive, unselected patients affected by MDR-O SSI were prospectively evaluated. In the same period, patients with non-MDR-O SSI and without SSI, matched for clinical and surgical data were used as control groups. Risk factors for infection, clinical outcome, and costs of care were compared by univariate and multivariate analysis. Among 3494 patients operated on during the study period, 47 presented an MDR-O SSI. Two control groups of 47 patients with non-MDR-O SSI and without SSI were identified. MDR-Os SSI were caused by poly-microbial etiology, meanly related to Gram negative Enterobacteriales. MDR-Os-SSI were related to major postoperative complications. At univariate analysis, iterative surgery, open abdomen, intensive care, hospital stay, and use of aggressive and expensive therapies were associated to MDR-Os-SSI. At multivariate analysis, only iterative surgery and the need of total parenteral and immune-nutrition were significantly associated to MDR-Os-SSI. The extra-cost of MDR-Os-SSI treatment was 150% in comparison to uncomplicated patients. MDR-Os SSI seems to be associated with major postoperative complications and reoperative surgery, they are demanding in terms of clinical workload and costs of care, they are rare but increasing, and difficult to prevent with current strategies.