Objectives: the aim of this pilot randomized split-mouth study was to evaluate and compare the clinical effects of two chlorhexidine-based gels delivered into periodontal pockets during initial periodontal therapy. Methods: Eight patients (four male and for female) suffering of chronic periodontitis and displaying each periodontal pockets deeper than 5 mm underwent a periodontal examination at baseline and after four weeks. This included the assessment of PI, BOP, PD, and CAL. PD and CAL were recorded at six sites per tooth. A total of 188 teeth were examined. The mean overall values of PD and CAL per quadrant were taken into account in this study. Each patient received SRP during initial therapy according to the one-stage Full Mouth Disinfection (Quirinen, 1995). In addition, each quadrant of the same arch was assigned to randomly receive a single subgingival application of either a novel chlorhexidine-based gel (Chlosite®, Ghimas s.p.a., Italy) or the chlorhexidine-gel PlakOut®, Santa Balanos, Greece). Subsequently, patients were advised to use 0,2% chlorhexidine mouthwashes (PlakOut®, Santa Balanos, Greece), twice a day, for the following four weeks, and OHI were reinforced. The Wilcoxon test was used to compare the differences between the baseline and four weeks after and for the differences between the groups. Results: Both therapies resulted in significant improvements in all clinical indices. At four weeks after application, in the Chlosite group the mean PD changed from 3.97±0.91 to 2.81±0.70 (p=0.012) and the CAL changed from 4.14±1.09 to 3.37±1.25 (p=0.03), while in the PlakOut group the PD changed from 3.88±0.77 to 2.78±0.53 (p=0.01) and the CAL changed from 4.02±0.96 to 3.42±1.01 (p=0.09). The Chlosite group resulted in slightly higher CAL gains (mean D=1.62 mm) and PD reductions (mean D=0.18 mm) than the PlakOut group, but these differences were not statistically significant due to the low number of cases. Conclusions: Following both initial therapy approaches, there were clinical improvements at four weeks from baseline. Additional topical subgingival application of Chlosite is safe and provided more favorable CAL gain and PD reduction than PlakOut. Keywords: initial periodontal therapy, chlorhexidine