The aim of this study was to compare the clinical and microbiological effect on Propionibacterium acnes of oral tetracycline plus topical adapalene vs. oral isotretinoin in moderate to severe acne vulgaris. Male and female acne patients with moderate or severe inflammatory disease were enrolled and assigned randomly to 6 months of treatment with oral tetracycline hydrochloride plus topical adapalene, or oral isotretinoin, in a controlled, open study. After cessation of oral treatment the antibiotic-treated group received topical adapalene for the 2-month follow-up period. Clinical and microbiological assessments were performed. Skin samples for microbial identification and quantification were taken at baseline, after 2, 4 and 6 months of treatment, and 2 months after cessation of treatment. Patients treated with isotretinoin showed prolonged significant remission compared with the other group. The density of resistant propionibacteria did not change significantly in any of the groups and there was no correlation between resistant P. acnes and the clinical response in any of the regions investigated. Antibiotic treatment was found to be a good alternative to isotretinoin, regardless of the presence of antibiotic-resistant P. acnes, although isotretinoin had a better effect, with prolonged remission after treatment.