48 adult patients with untreated periodontitis harboring subgingival Actinobacillus actinomycetemcomitans and/or Porphyromonas gingivalis as assessed by PCR were randomly assigned to receive full-mouth scaling alone (control) or scaling with systemic metronidazole plus amoxicillin and supragingival irrigation with chlorhexidine digluconate (test). In patients harboring A. actinomycetemcomitans intraorally at baseline, the adjunctive antimicrobial therapy resulted in a significantly higher incidence of probing attachment level (PAL) gain of 2 mm or more compared to scaling alone over 12 months (p<0.05). In addition, suppression of A. actinomycetemcomitans in subgingival plaque below detectable levels was associated with an increased incidence of PAL gain. In contrast, patients initially harboring P. gingivalis but not A. actinomycetemcomitans in the oral cavity showed a significantly higher incidence of PAL loss following adjunctive antimicrobial therapy compared to scaling alone (p<0.05). When the presence of pathogens at baseline was disregarded in the analysis, adjunctive antimicrobial therapy did not significantly enhance clinical treatment outcome. The results indicated that adults with untreated periodontitis harboring A. actinomycetemcomitans may benefit from the adjunctive antimicrobial therapy for a minimum of 12 months, whereas, the regimen may adversely affect the clinical treatment outcome of patients harboring P. gingivalis but not A. actinomycetemcomitans.