BACKGROUND It has been suggested that scaling and root planing of all pockets within a few hours and chlorhexidine treatments (full-mouth disinfection) may reduce the need for supplementary therapies. The aim of this study was to evaluate the clinical benefit of amoxicillin and metronidazole administered immediately after completion of full-mouth periodontal debridement in patients with chronic periodontitis. METHODS This was a single-center, double-masked, placebo-controlled, randomized longitudinal study of 6 months' duration. Fifty-one patients received full-mouth periodontal debridement, performed within 48 hours. Twenty-five subjects received metronidazole, 500 mg, and amoxicillin, 375 mg, three times a day for 7 days; 26 subjects received a placebo. RESULTS Forty-seven patients could be followed up to month 6. No differences in clinical parameters were noted before treatment. The overall mean probing depth decreased from 4.3 +/- 0.4 mm to 3.0 +/- 0.2 mm in the test group and from 4.4 +/- 0.4 mm to 3.1 +/- 0.3 mm in the control group (P = 0.05, difference between groups). More importantly, test subjects had a significantly lower mean number of persisting pockets >4 mm and bleeding on probing that required further treatment (P = 0.005): 6 months after full-mouth debridement plus antibiotics, only 0.4 +/- 0.8 persisting pockets were still present, whereas 3.0 +/- 4.3 persisting pockets were still present in the control group. The protective risk of the antibiotics for having more than one pocket deeper than 4 mm and bleeding on probing per subject after 6 months was 8.85. CONCLUSIONS Systemic metronidazole and amoxicillin significantly improved the 6-month clinical outcomes of full-mouth non-surgical periodontal debridement, thus significantly reducing the need for additional therapy.