Data concerning treatment outcomes in patients with generalized aggressive periodontitis (GAgP) are limited. The aim of this study is to investigate 6-month clinical and microbiologic outcomes of the one-stage full-mouth disinfection (OSFMD) in the management of patients with GAgP. Twenty-seven patients with advanced GAgP were included in this prospective follow-up intervention study. Clinical and microbiologic parameters were collected at baseline and 3 and 6 months after the OSFMD. Patient-, tooth-, and site-level analyses were carried out. Subgingival samples from moderate (4 to 5 mm) and deep (≥6 mm) pocket sites were analyzed using a polymerase chain reaction for Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans), Prevotella intermedia, Porphyromonas gingivalis, Tannerella forsythia (previously T. forsythensis), and Treponema denticola. The OSFMD resulted in significant improvements in all parameters. After 6 months, the whole-mouth probing depth (PD) decreased from 4.2 ± 1.1 mm to 2.8 ± 0.6 mm, and the clinical attachment level was reduced from 4.5 ± 1.2 mm to 3.4 ± 1.1 mm (P <0.001). When data were analyzed based on the frequency distribution of PD, the number of sites with PD ≥5 mm decreased by 61% from baseline values, and mean PD reductions of 1.5 and 2.5 mm were noted in moderate and deep pockets, respectively. At 6 months, percentages of moderate and deep sites free of pathogens were 40% and 27%, respectively. The OSFMD may be a viable approach to deal with severe GAgP.