A randomized, double-blind, clinical study was done to assess the microbiological and clinical effects of metronidazole plus amoxicillin (M+A) as the only therapy in 46 patients with moderate to advanced progressive adult periodontitis. Patients were included in the study after at least 2 sites showed ≥2 mm clinical attachment loss. Bleeding on probing, probing depth, and clinical attachment level were measured using on automated probe. The percentage of surfaces with plaque was recorded at day 0, and at 2 and 4 months after therapy. No effort was made to change the oral hygiene habits of patients. Identification of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella intermedia was assessed utilizing DNA technology at day 0 and 2 months after therapy. Twenty-three patients received metronidazole 250 mg plus amoxicillin 500 mg, 3 times/day for a week and 23 a placebo. Two patients in the placebo group were dropped at 2 months because they had taken antibiotics for medical reasons. Statistical analyses of differences between groups was done using the Mann-Whitney test, and the differences within each group were tested with ANOVA. There were no significant changes in surfaces with plaque in either group after therapy. The percentage of bleeding sites decreased significantly from baseline to 2 and 4 months in the M+A group (P = 0.001), and increased in the placebo group. Differences in bleeding on probing between groups were significant at 2 (P = 0.018), and 4 months (P = 0.005). The mean attachment level values at 2 and 4 months posttherapy improved significantly in the M+A group compared to the placebo group (P = 0.001). Treatment with M+A resulted in a significant mean reduction in probing depth at 2 and 4 months compared to baseline values (P = 0.001). The M+A group showed a significant reduction of sites with high levels of Pg (P = 0.001) at 2 months compared with baseline values, and there was a significant reduction of sites with Pg and Pi in the M+A group compared with the placebo group. The results showed that a combined M+A treatment as the only therapy changes the proportion of some subgingival microorganisms and allows a significant improvement in clinical conditions. J Periodontol 1998;69:1291–1298.