BACKGROUND: In the last few years knowledge about periodontal infections has increased enormously, nevertheless practitioners are still seeking guidelines for suitable treatment concepts. METHODS: The aim of this study was to examine the effect of doxycycline, metronidazole, and clindamycin used adjunctively in a 2-step nonsurgical procedure in patients with rapidly progressive periodontitis (RPP). The first step included scaling, root planing, and polishing (SRP) in each quadrant using 4 to 5 visits. The second step included full-mouth enhanced root planing (RP) and wound dressing in 1 or 2 visits after SRP and the beginning of antibiotic therapy. Forty-eight patients (mean age 32.4 years) with generalized RPP, with an average of 16 sites with probing depths (PD) deeper than 8 mm, and high counts of Porphyromonas gingivalis were randomly assigned to 4 different groups: group 1 (doxycycline) n = 12, group 2 (metronidazole) n = 15, group 3 (clindamycin) n = 11, and group 4 (control group; no antibiotic treatment) n = 10. Clinical evaluations, including plaque index (PI), sulcus bleeding index (SBI), probing depth (PD), clinical attachment level (CAL), and bacteriological and crevicular cell sampling, were done at baseline (BL), 3 weeks after SRP, and 6 and 24 months after RP. RESULTS: After the first step (SRP), we observed an improvement of PI and SBI in all 4 groups, but did not see any statistically significant PD reduction 3 weeks after SRP compared to baseline. However, 6 and 24 months after the second step (RP) we observed a significantly greater reduction of PD in groups 2 and 3 and a significantly greater CAL gain in comparison to groups 1 and 4. After 24 months, the attachment level gain in group 1 and group 4 was less than 1.5 mm, and less than 1.0 mm in PD site categories 6 to 9 mm and >9 mm. PI showed no significant difference between the groups throughout the period after SRP until 24 months, compared to 3 weeks after SRP. SBI decreased most in the metronidazole and clindamycin groups. P. gingivalis and Actinobacillus actinomycetemcomitans were almost completely eradicated in these 2 groups 24 months after RP. In addition, the phagocytotic capacity of crevicular polymorphonuclear neutrophils was increased in groups 2 and 3 after the second step. CONCLUSIONS: The present results show that metronidazole and clindamycin are effective antibiotics when used adjunctively in a 2-step nonsurgical procedure of scaling and root planing in RPP patients.