Infection is among the first reasons for failure of orthopedic implants. Various antibacterial coatings for implanted biomaterials are under study, but only few technologies are currently available in the clinical setting. Previous studies showed the in vitro and in vivo efficacy and safety of a fast resorbable (<96 h) hyaluronic and polylactic acid based hydrogel, loaded with antibiotic or antibiofilm agents (DAC®, Novagenit Srl, Mezzolombardo, TN). Aim of this study is to report the results of the largest clinical trial in trauma and orthopedic patients. In this prospective, controlled, study, a total of 184 patients (86 treated with internal osteosinthesis for closed fractures and 98 undergoing cementless total hip or knee joint prosthesis) were randomly assigned in three European orthopaedic centers to receive antibiotic-loaded DAC coating or to a control group, without coating. Pre- and post-operative assessment of laboratory tests, wound healing (ASEPSIS score), clinical score (SF-12 score) and x-rays were performed at fixed time intervals. Statistical analysis was performed with Fisher exact test or Student's t test. Significance level was set at p<0.05. The study was approved by the local Ethical Committee and all patients provided a written informed consent. On average, wound healing, clinical scores, laboratory tests and radiographic findings did not show any significant difference between the two-groups at a mean 12 months follow-up (min: 6, max: 18 months). Four surgical site infections and two delayed union were observed in the control group compared to none in the treated group. No local or systemic side effects, that could be related to DAC hydrogel coating, were noted and no detectable interference with bone healing or osteointegration could be found This is the largest study, with the longest follow-up, reporting on clinical results after the use of a fast-resosrbable anti-bacterial hydrogel coating for orthopaedic and trauma implants. Our results show the safety of the tested coating in different indications; although not statistically significant, the data also show a trend towards surgical site infection reduction, as previously demonstrated in the animal models.