This randomized, split-mouth, controlled clinical study assessed the additional clinical benefits of a local desiccant antimicrobial agent (HY) combined with subgingival mechanical instrumentation (SRP) vs. SRP alone in treating severe periodontitis. Patients with stages III and IV periodontitis received full-mouth periodontal examinations at baseline and after a three-month follow-up. Two randomly selected hemiarches in each periodontitis patient were treated with SRP plus HY and were included in the test group, while the other two hemiarches received only SRP and were included in the control group. In thirty patients, the analyses of the evolution of the periodontal parameters over time showed statistically significant mean differences for the probing depths and clinical attachment level values resulting from all the examined sites, as well as from the interproximal sites (p< 0.001) in both the test and control groups. The intergroup comparisons of the same four parameters showed no significant differences (p= 0.322,p= 0.36,p= 0.516, andp= 0.509, respectively). Based on these study results, no additional benefits were obtained after HY subgingival applications.