Surgical site infections (SSIs) are mainly caused byStaphylococcus aureus(S. aureus) andStaphylococcus epidermidis(S. epidermidis) biofilms. Biofilms are aggregates of bacteria embedded in a self-produced matrix that offers protection against antibiotics and promotes the spread of antibiotic-resistance in bacteria. Consequently, antibiotic treatment frequently fails, resulting in the need for alternative therapies. The present study describes thein vitroefficacy of the Cu(DDC)2complex (2:1 M ratio of diethyldithiocarbamate (DDC−) and Cu2+) with additional Cu2+againstS. aureusandS. epidermidisbiofilms in models mimicking SSIs andin vitroantibacterial activity of a liposomal Cu(DDC)2+ Cu2+formulation. Thein vitroactivity onS. aureusandS. epidermidisbiofilms grown on two hernia mesh materials and in a wound model was determined by colony forming unit (CFU) counting. Cu2+-liposomes and Cu(DDC)2-liposomes were prepared, and their antibacterial activity was assessedin vitrousing the alamarBlue assay and CFU counting andin vivousing aGalleria mellonellainfection model. The combination of 35 μM DDC−and 128 μM Cu2+inhibitedS. aureusandS. epidermidisbiofilms on meshes and in a wound infection model. Cu(DDC)2-liposomes + free Cu2+displayed similar antibiofilm activity to free Cu(DDC)2+ Cu2+, and significantly increased the survival ofS. epidermidis-infected larvae. Whilst Cu(DDC)2+ Cu2+showed substantial antibiofilm activityin vitroagainst clinically relevant biofilms, its application in mammalianin vivomodels is limited by solubility. The liposomal Cu(DDC)2+ Cu2+formulation showed antibiofilm activityin vitroand antibacterial activity and low toxicity inG. mellonella, making it a suitable water-soluble formulation for future application on infected wounds in animal trials.