Aim: To evaluate the clinical non-inferiority of a 3-day protocol of systemic antibiotics adjunctive to subgingival instrumentation (SI) compared with a 7-day-protocol in patients with Stage III/IV Grade C periodontitis., Materials and Methods: Fifty systemically healthy patients (32.7 ± 4.3 years) with aggressive periodontitis (AgP; Stage III/IV Grade C periodontitis) were treated by SI and adjunctive amoxicillin and metronidazole and were randomly assigned to Group A: (n = 25) 500 mg antibiotics (AB) 3 times a day for 3 days, followed by placebo 3 times a day for 4 days, or Group B: (n = 25) 500 mg AB 3 times a day for 7 days. Clinical, microbial, and immunological parameters were assessed at baseline, 3 months, and 6 months, and patient-related outcomes were assessed after 2 weeks. The primary outcome variable was the number of residual sites with pocket depth (PD) ≥6 mm at 6 months., Results: For the primary outcome variable (the number of residual sites with PD ≥6 mm at 6 months), the null hypothesis was rejected and non-inferiority of the 3-day AB protocol compared with the 7-day AB protocol was demonstrated (the upper limits of the 95% confidence interval for intention to treat analysis: [-2.572; 1.050] and per protocol analysis: [-2.523; 1.318] were lower than the assumed margin of Δ = 3.1). Comparable clinical improvements were obtained for all parameters with both antibiotic protocols (p > .05). All investigated periodontopathogens and pro-inflammatory host-derived markers were statistically significantly reduced without differences between the treatments (p > .05)., Conclusions: These findings indicate that in patients with AgP (Stage III/IV Grade C periodontitis), a 3-day systemic administration of amoxicillin and metronidazole adjunctive to SI may lead to non-inferior clinical outcomes after 6-months with fewer adverse events compared with a 7-day-protocol., (© 2022 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)