Background: This study's aim was to evaluate the local effect of clarithromycin associated with antimicrobial photodynamic therapy (aPDT) in the treatment of generalized aggressive periodontitis. Materials and methods: The study sample comprised 72 periodontal pockets on single-rooted teeth in multiple quadrants, with both probing depth and clinical attachment level >= 5 mm, and with bleeding on probing. The pockets were randomly distributed into four groups (n = 18 each) that received ultrasonic periodontal debridement in addition to placebo (the UPD group), systemic clarithromycin (the UPD + CLM group), aPDT (the UPD + aPDT group), or both systemic clarithromycin and aPDT (the UPD + CLM + aPDT group). The measurements were performed prior to treatment (baseline) and at 3 and 6 months postoperatively. The following parameters were evaluated: plaque index, bleeding on probing, probing depth, gingival recession, and clinical attachment level. A 5% significance level was used in the statistical analysis. Results: At 3 months, UPD + aPDT, UPD + CLM, and UPD + CLM + aPDT groups all exhibited reduced probing depths relative to the UPD group (p < 0.05). However, at 6 months, the reduction in mean probing depth was greater in the antibiotic groups (UPD + CLM and UPD + CLM + aPDT) than in the UPD and UPD + aPDT groups (p < 0.05). Regarding clinical attachment level, only the UPD + CLM + aPDT group presented a significant gain relative to the UPD and UPD + PDT groups (p < 0.05). Conclusions: Ultrasonic periodontal debridement has greater clinical advantages when associated with clarithromycin than with associated with aPDT. However, the joint application of aPDT and clarithromycin did not present additional benefits.