Hydrocolloid technology has been proven effective in treating dermal wounds. A previous study showed that a newly developed thin hydrocolloid patch [Compeed cold sore patch (CSP)] provided multiple wound-healing benefits across all stages of a herpes simplex labialis (HSL) outbreak. An assessment of CSP efficacy and safety was conducted in an international, multicentre, assessor-blinded study, which enrolled 728 subjects with a history of recurrent HSL. Of these, 351 experienced an HSL outbreak and were randomized to use CSP (n = 179) or acyclovir cream 5% (n = 172) at the onset of symptoms until the lesion healed, for a maximum of 10 days. The primary end point was the subject's global assessment of therapy (SGAT; 0-10 scale; 0 = no response, 10 = excellent response). Multiple secondary end points included clinician-assessed healing time and subject assessment of lesion protection, noticeability and social embarrassment. CSP and acyclovir were highly effective (mean SGAT = 7.89 and 8.00, respectively), with no significant difference observed (P = 0.65). The difference in healing times between products was not significant (median, 7.57 days with CSP vs. 7.03 days with acyclovir, P = 0.37). Both treatments were well tolerated. CSP using hydrocolloid technology provides an efficacious and safe alternative to topical antivirals in treating HSL as a wound while affording additional immediate benefits of wound protection, discretion and relief of social embarrassment.