Porphyromonas gingivalis gingipains is suspected to be one of the most important causative agents of periodontitis. We postulated that the inhibition of gingipains may reduce the pathogenic nature of P. gingivalis. Anti-P. gingivalis egg yolk antibody (IgY-GP) was isolated from the yolks of hens immunized with purified gingipains. We applied IgY-GP gel subgingivally in periodontitis patients who harbored P. gingivalis in their subgingival flora. Five pairs of contralateral anterior single-rooted teeth were selected. One tooth in each contralateral pair was randomly treated with IgY-GP and subgingival scaling and root planing, whereas the other tooth was treated with SRP alone. The number of P. gingivalis bacteria was assessed by real-time PCR. Bacterial levels were expressed as the percentage of total bacteria. The IgY-GP group had a significant reduction in probing depth. BOP significantly decreased in the IgY-GP group compared to the control group at week 4. The levels of P. gingivalis significantly increased in the control group at week 4, whereas the reduction in the levels of P. gingivalis was sustained in the IgY-GP group. Within the limitations of the present study, IgY-GP was shown to be an effective immunotherapeutic agent in the treatment of periodontitis.