OBJECTIVE: To compare the efficacy and safety of negatively-charged polystyrene microspheres (NCM)with controls (saline soaks) in the treatment of hard-to-heal wounds of various aetiologies. METHOD: Patients with one or more hard-to-heal wounds, defined as refractory to healing for at least 4 weeks, or those with exposed bone, tendon or ligament, were eligible for inclusion and were randomised to either NCM (PolyHeal; MediWound Ltd.) or controls, both applied twice daily for 4 weeks. Patients were monitored bi-weekly for an additional 8 weeks, while treated by standard wound care, at the investigators' discretion, and were re-evaluated 2 years after inclusion. The primary endpoint was defined as coverage of> 75% of the wound area by light-red granulation tissue after 4 weeks of treatment. RESULTS: Fifty-eight patients completed the study, 32 in the NCM group and 26 in the control group. The two most common wound types were those with primary etiologies of venous insufficiency and postoperative/post trauma. In the NCM group 47% of patients achieved > 75% light red granulation tissue after 4 weeks compared with 15% of patients in the control group (p=O.O I). The mean wound surface area in the NCM group was reduced by 39.0% after 4 weeks compared with 14.9% in the control group (p=0.02).The achievement of> 75% light red granulation tissue and reduction of mean wound surface area was also observed in the two main sub-groups (venous insufficiency and postoperative/post trauma), although it was not statistically significant, possibly due to the small sample size in each sub-group. CONCLUSION: This study demonstrates that compared to control treatment, NCM treatment of hard to-heal and chronic wounds improves formation of healthy granulation tissue and reduces wound size thus in fact 'kick-starting' the healing process and 'dechronifying' chronic wounds.