Surgical site infections are the second most common hospital- and community-acquired Gram-positive infections, with the US Centers for Disease Control and Prevention estimating that about 500 000 surgical site infections occur annually in the USA. The aim of this work was to determine the in vitro activity of the saponin diosgenyl 2-amino-2-deoxy-β-d-glucopyranoside hydrochloride (HSM1) and its bactericidal effect for a large number of Gram-positive cocci, as well as to investigate its in vitro interaction with seven clinically used antibiotics. In vivo, a wound model was established through the panniculus carnosus of BALB/c mice and then inoculated with 5×10(7) c.f.u. Staphylococcus aureus or Enterococcus faecalis. For each bacterial strain, the study included an infected or non-infected group that did not receive any treatment, a group treated with local HSM1, a group treated with intraperitoneal vancomycin, a group treated with intraperitoneal daptomycin and two groups that received HSM1 local treatment plus intraperitoneal vancomycin or daptomycin. All isolates were inhibited by HSM1 at concentrations of 2-32 mg l(-1). Synergy was demonstrated when HSM1 was combined with vancomycin and daptomycin. In in vivo studies, all groups treated with single drugs showed a statistically significant result compared with the control group. The two groups treated with drug combinations showed the highest antimicrobial efficacy. The good in vitro activities and the in vivo efficacy suggest HSM1 as a promising therapeutic candidate in Gram-positive wound infections.