For the treatment of periodontitis stage III/IV, a quadrant/week-wise debridement (Q-SRP) was compared with three full-mouth approaches: full-mouth scaling (FMS, accelerated Q-SRP within 24 h), full-mouth scaling with chlorhexidine-based disinfection (FMD), and FMD with adjuvant erythritol air polishing (FMDAP). The objective of this prospective, randomized study (a substudy of ClinicalTrials.gov, identifier: NCT03509233) was to compare the clinical and microbiological effects of the treatments. In total, 105 patients were randomized to one of the four aforementioned treatment groups, with n = 25, 28, 27, and 25 patients allocated to each group, respectively. At baseline and 3 and 6 months after treatment, the clinical parameters, including the pocket probing depths, clinical attachment level, and bleeding on probing, were recorded, and the prevalence of the total bacteria and four periodontal pathobionts (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, and Tannerella forsythia) was determined using real-time quantitative PCR. Concerning the clinical outcomes, all the treatment modalities were effective, but the full-mouth approaches, especially FMDAP, were slightly superior to Q-SRP. Using the FMD approach, the reduction in the bacterial load and the number of pathobionts was significantly greater than for FMS, followed by Q-SRP. FMDAP was the least effective protocol for microbial reduction. However, after a temporary increase 3 months after therapy using FMDAP, a significant decrease in the key pathogen, P. gingivalis, was observed. These findings were not consistent with the clinical results from the FMDAP group. In conclusion, the dynamics of bacterial colonization do not necessarily correlate with clinical outcomes after full-mouth treatments for periodontitis stage III/IV.