Propionibacteria resistant to high concentrations of erythromycin [minimal inhibitory concentration (MIC) > or = 0.5 mg/ml] are now commonly isolated from the skin of antibiotic-treated acne patients. This double-blind study was carried out to assess the ability of 4% w/v erythromycin with and without 1.2% w/v zinc acetate to reduce the numbers of erythromycin-resistant propionibacteria in vivo, and also to monitor the acquisition of resistant strains de novo during therapy. Under laboratory conditions, erythromycin-resistant propionibacteria were shown to be as sensitive to zinc acetate as fully sensitive strains. In vivo, the erythromycin/zinc complex and erythromycin alone produced highly significant reductions in total propionibacteria (P < 0.001) and in the number of erythromycin-resistant strains (P < 0.001 at 8 weeks). After 12 weeks, resistant propionibacteria were reacquired, or acquired de novo, by three patients treated with erythromycin alone and four patients treated with the erythromycin/zinc complex. In contrast, changes in numbers of Micrococcaceae were slight and, after 12 weeks, erythromycin-resistant strains were predominant in both treatment groups. In vitro MIC determinations suggested that this finding might be explained by the exceptionally high degree of erythromycin resistance displayed by some staphylococcal strains (MIC > 4 mg/ml) and by the relative insensitivity of all staphylococcal strains to zinc acetate. Erythromycin with and without zinc was clinically effective, and both preparations produced significant reductions in acne grade, and inflamed and non-inflamed lesion counts (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)