Extrinsic and intrinsic pathways of apoptosis are involved in generalized aggressive periodontitis (GAgP). The aim of this study was to evaluate 6-month clinical outcomes relative to apoptosis of one-stage full-mouth disinfection (OSFMD) and systemic antibiotics (SA) in the treatment of GAgP. Twenty-six patients with GAgP were included in this prospective follow-up intervention study. Gingival crevicular fluid (GCF) was collected from patients at baseline and 3 and 6months after periodontal therapy, which consisted of OSFMD and SA (amoxicillin and metronidazole, 500mg each for 7days). The levels of p53, caspase-3, TNF-α, TRAIL, IL-1β, and IL-10 in GCF were measured via ELISA. Periodontal parameters were improved at 3 and 6months compared to baseline (p<0.05). p53 was decreased up to 6months (p<0.05). TRAIL, TNF-α, and IL-10 were similar at baseline and 3 and 6months. Caspase-3 and IL-1β were decreased at 3months (p<0.05), but similar at 6months compared to baseline (p>0.05). Although OSFMD plus SA improves clinical periodontal parameters up to 6months, this treatment protocol differentially regulates the apoptosis markers caspase-3 at 3months and p53 at 6months without influencing TRAIL in GCF.