Background: The aim of the present study is to evaluate the periodontal clinical and microbiologic responses and possible adverse effects of clarithromycin (CLM) combined with periodontal mechanical therapy in the treatment of patients with generalized aggressive periodontitis.Methods: Forty patients were selected and randomly assigned into one of two groups: 1) CLM (n = 20): one‐stage full‐mouth ultrasonic debridement (FMUD) associated with CLM (500 mg, every 12 hours for 3 days); and 2) placebo (n = 20): FMUD associated with placebo pills. Clinical and microbiologic parameters were evaluated at baseline and 3 and 6 months postoperatively.Results: Both treatments presented statistically significant clinical and microbiologic improvements. However, the CLM group presented lower means of probing depth for pockets ≥7 mm at 6 months (4.0 ± 1.7 mm) compared with the placebo group (4.7 ± 1.3 mm) (P = 0.04). In addition, the CLM group also presented greater reduction of Porphyromonas gingivalis (Pg) DNA counts at 6 months (P = 0.0001).Conclusion: Results from this study suggest both treatments are effective; however, adjunct use of CLM to FMUD leads to better reduction of deep pockets and Pg at 6 months compared with FMUD alone.