The combination of systemic metronidazole (MTZ) and amoxicillin (AMX) to scaling and root planing (SRP) has shown to be a promising periodontal treatment. However, some essential issues associated with the use of these antibiotics remain to be established. Although these agents are often prescribed after the healing phase of the SRP procedure, there is biological plausibility to support its use in conjunction with the mechanical treatment. However, to date, no placebo controlled randomized clinical trial (RCT) has directly compared these two protocols. Therefore, the aim of this multicentric RCT is to compare the clinical, microbiological and immunological effects of adjunctive systemic MTZ+AMX administered in different phases of the treatment of generalized chronic periodontitis (GChP). 180 subjects with GChP will be randomly assigned into three groups (n=60/group) that will receive SRP-only (control group) or in combination with 400 mg MTZ+500 mg AMX beginning at the first SRP session (group test 1) or after 3 months of its completion (group test 2). All volunteers will receive clinical and microbiological evaluation at baseline, 3, 6 and 12 months, and immunological assessment (levels of 20 chemokines) at baseline and 12 months post-therapy. Nine subgingival biofilm samples will be collected by subject and analyzed for counts and proportions of 40 bacterial species by checkerboard DNA-DNA hybridization. Differences in clinical, microbiological and immunological parameters among groups and over time will be evaluated using the ANOVA, ANCOVA, Chi-square and Tukey tests. Microbiological analyzes will be performed using adjustments for multiple comparisons. Statistical significance will be set at 5%.