The purpose of this randomized, double-blind, placebo-controlled multicenter trial was to compare topical zinc oxide with placebo mesh on secondary healing pilonidal wounds. Sixty-four (53 men) consecutive patients, aged 17-60 years, were centrally randomized to either treatment with 3% zinc oxide (n = 33) or placebo (n = 31) by concealed allocation. Patients were followed with strict recording of beneficial and harmful effects including masked assessment of time to complete wound closure. Analysis was carried out on an intention-to-treat basis. Median healing times were 54 days (interquartile range 42-71 days) for the zinc and 62 days (55-82 days) for the placebo group (p = 0.32). Topical zinc oxide increased (p < 0.001) wound fluid zinc levels to 1,540 (1,035-2,265) microM and decreased (p < 0.05) the occurrence of Staphylococcus aureus in wounds. Fewer zinc oxide (n = 3) than placebo-treated patients (n = 12) were prescribed postoperative antibiotics (p = 0.005). Serum-zinc levels increased (p < 0.001) postoperatively in both groups but did not differ significantly between the two groups on day 7. Zinc oxide was not associated with increased pain by the visual analog scale, cellular abnormalities by histopathological examination of wound biopsies, or other harmful effects. Larger clinical trials will be required to show definitive effects of topical zinc oxide on wound healing and infection.