Aim To evaluate subgingival instrumentation (SI) in periodontitis stage III and IV, grade B and C with systemic antibiotics (AB) only after detection of Aggregatibacter actinomycetemcomitans. Materials and Methods Patients of the Department of Periodontology of Goethe University Frankfurt/Germany were screened for microbiological testing between 2008 and 2018. All patients with aggressive and generalized severe chronic periodontitis were tested. In case of positive subgingival A. actinomycetemcomitans tests, SI was combined with AB; in all other cases it was not (nAB). Clinical examinations were performed before (T0), 12.4 (9.4/15.1) weeks after SI (T1), and at the last supportive periodontal care (T2; 3.1 [1.4/5.5] years after T1). Results at T1/T2 were assessed as “treat‐to‐target” endpoint (≤4 sites with probing pocket depths ≥5 mm). Results Four‐hundred and twenty‐five patients (280 stage III/145 stage IV, 95 grade B/330 grade C) provided complete data (AB 144/nAB 281) for T0 and T1, and 332 (AB 121/nAB 211) for T2. At T1/T2, AB resulted in 53 (37%)/76 (63%) patients with “treat‐to‐target” endpoint, and nAB in 76 (27%)/91 (43%) (p = .038/.001). Conclusions In periodontitis stage III and IV, grade B and C with subgingival A. actinomycetemcomitans infection, SI with AB resulted in higher rate of “treat‐to‐target” endpoint than exclusive SI in patients without the infection.