OBJECTIVES: To evaluate the quality of published evidence of oral antibiotic and isotretinoin therapies in the treatment of moderate to severe acne. METHODS: A systematic search of published literature was conducted using PubMed and Embase using key word “acne” and therapy names doxycycline; tetracycline; minocycline; erythromycin; sulfamethoxazole-trimethoprim (SMXTMP); azithromycin; isotretinoin; and tretinoin.  Studies evaluating topical retinoids and oral antimicrobials were also included. No date restrictions were used in order to capture all relevant studies. Studies were eligible for inclusion if they meet the following criteria: 1) randomized or observational clinical evaluations in humans; 2) published in English; 3) duration of 8 week period or greater; and 4) evaluated at least 5 subjects. After title and abstract review, relevant citations were obtained and reviewed for inclusion.  Data was abstracted into a standardized data collection form by one author and verified by another.  Study quality was rated using the Jadad scale.    RESULTS: A total of 588 articles were identified, but only 164 studies met all inclusion criteria.   The mean (SD) minimum age was 14.2 (2.32) and study duration was 19 weeks (SD=39).  On average the sample size per treatment arm was 92 (SD=176).  Study designs included: crossover (6); observational (69); randomized-controlled trial (82), non-randomized (1) and not reported/unknown (6). The number of studies evaluating the various treatments were: azithromycin (16); doxycycline (24); erythromycin (20); isotretinoin (86); minocycline (40); SMXTMP (2); and tetracycline (47).  A total of 204 studies were RCTs, with 57 (28.1%) reporting intention-to-treat and 146 (71.9%) per-protocol results.  Among RCTs, the mean (SD) Jadad score was 2.75 (1.50) for azithromycin; 2.81 (1.76) for doxycycline; 4.00 (1.04) for erythromycin; 2.80 (1.52) for isotretinoin; 3.32 (1.35) for minocycline; and 3.57 (1.02) for tetracycline.    CONCLUSIONS: In general, the quality of randomized controlled trials evaluating antibiotic treatments for moderate to severe acne is variable.