Objective: Adjunctive antimicrobials improve probing depth and clinical attachment loss compared with subgingival debridement (SD) alone in patients with aggressive periodontitis. The microbiologic and clinical effectiveness of moxifloxacin (MOX) and amoxicillin plus metronidazole (AMOX+ME) as adjunctive therapies for generalized aggressive periodontitis were compared. Method and materials: This pilot randomized controlled clinical trial included 36 patients who were assigned to one of three therapy groups: SD plus systemic MOX (400 mg QD for 7 days), SD plus systemic AMOX+ME (500 mg TID each for 7 days), or SD plus placebo. Probing depth, clinical attachment loss, bleeding on probing, and plaque were recorded at baseline and 3 and 6 months after treatment. Subgingival plaque samples were analyzed. Results: All treatments resulted in significant probing depth and clinical attachment loss reduction compared with the baseline values (P .0001 for all), with the effects still present at 6 months posttreatment, but the patients taking antibiotic protocols presented the most significant gains (P .0001). There was a significant reduction in the occurrence of gingival pockets ≥ 6 mm at 6 months in all treatment groups (P .0001), favoring the MOX and AMOX+ME groups. Adjunctive MOX diminished subgingival Aggregatibacter actinomycetemcomitans to unnoticeable stages, after the follow-up period. Adverse events were noted only in some patients of the AMOX+ME group. Conclusions: This pilot clinical trial proposes that using MOX and AMOX+ME as adjuncts to SD improves the clinical and microbiologic parameters in comparison to mechanical therapy alone; however, the MOX protocol did not cause adverse events and decreased subgingival A actinomycetemcomitans to imperceptible levels. Keywords: amoxicillin, generalized aggressive periodontitis, metronidazole, moxifloxacin, randomized controlled clinical trial