Mechanical debridement results in a shift of the bacterial composition in the periodontal pocket on the species level. It is unknown, however, whether a clonal change within a species could lead to the emergence of strains with different levels of virulence. Therefore, in the present study, the genetic variability of Actinobacillus actinomycetemcomitans was assessed and strains identified which were associated with periodontal disease progression following periodontal therapy, i.e., refractory periodontitis. Twenty adult patients with untreated periodontitis and subgingival colonization of A. actinomycetemcomitans were randomly assigned to receive full-mouth scaling alone or scaling with an adjunctive antimicrobial therapy. Both groups received supportive periodontal therapy at 3, 6, 9, 12, 18, and 24 months. Subgingival plaque samples were taken at every visit; venous blood was obtained at 24 months only. A. actinomycetemcomitans isolates were typed by the RAPD method, and antibody reactivity against outer membrane proteins was assessed by immunoblot analysis. Eleven distinct RAPD patterns were found in 18 patients completing the study. All patients harbored only one A. actinomycetemcomitans genotype, and within each patient this genotype persisted throughout the 24-month observation period. No differences in the expression of antibody reactivity against outer membrane proteins were found between strains isolated at baseline and at 24 months. Three genotypes were associated with reduced survival rates of teeth without probing attachment loss of 2 mm or more. The results indicated that (i) most patients harbored only one A. actinomycetemcomitans genotype; (ii) the genotype persisted following therapy; and (iii) only some genotypes were associated with refractory periodontitis.