Abstract The effectiveness of azithromycin combined with full-mouth scaling procedures was compared to quadrant-wise scaling combined with the same dosage of azithromycin when treating periodontitis patients over a 6-month period. In this randomized clinical trial study, thirty-four individuals diagnosed with generalized stage III and IV periodontitis underwent baseline, 3-month, and 6-month post-treatment examinations. The study population was randomly assigned to either full-mouth scaling (FMS) or quadrant-wise scaling and root planning (QSRP) in addition to their taking of systemic azithromycin (500 mg/day) for three consecutive days. Periodontal probing depth (PD), clinical attachment level (CAL), gingival index (GI), and plaque index (PI) were monitored along with the quantification of total bacterial load and red complex bacterial species (Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola) in subgingival samples by real time polymerase chain reaction. The volume of gingival crevicular fluid (GCF) was also monitored over time. The primary outcomes included improvements of PD and CAL. Data was statistically analyzed through a repeated-measures analysis of variance (ANOVA) test, multiple least significant difference (LSD) comparisons, Kruskal-Wallis, Friedman, and paired Student t-tests (p<0.05). FMS and QSRP provided similar PD, CAL, GI, PI, and GCF improvements. After treatment, the FMS group displayed lower mean values of total bacterial load and red complex bacterial species in comparison to the QSRP group. FMS and QSRP in conjunction with systemic azithromycin appeared to be an effective and reliable short-term therapeutic approach for the treatment of generalized stage III and IV periodontitis. However, FMD demonstrated superiority in regard to the 6-month antibacterial effects when compared to QSRP.