Objectives: To evaluate and compare the effect of nonsurgical periodontal therapy in conjunction with 2 different antibacterial agents on clinical and immunological parameters in aggressive periodontitis (AgP) patients. Method and Materials: Thirty-one AgP patients underwent clinical examination that included plaque index (PI), gingival index (GI), probing pocket depth (PPD), and clinical attachment level (CAL). GCF (gingival crevicular fluid) samples were collected and assayed for PGE2, IL-1ß, and TNFα. Nonsurgical periodontal therapy was performed. The patients received doxycycline (doxy group) or metronidazole plus amoxicillin (am-met group). After completion of the mechanical phase of therapy, patients were seen biweekly for oral hygiene reinforcement. After 12 weeks, clinical measurements and GCF sampling were repeated. Results: The combined mechanical and antimicrobial therapy resulted in overall improvement in all clinical parameters; mean PPD reduction of 0.74 ± 0.1 mm and mean CAL gain 0.86 ± 0.1 mm were both statistically significant (P = .0001). Marked reduction was observed for PGE2 and IL-1ß, but not TNFα. There was no significant difference between the 2 groups at baseline or final examination, except for PGE2 at final examination: It was significantly lower for the doxy group (83.61 ± 5.8 ng) than for the am-met group (124.08 ± 15.8 ng), P = .0202. Conclusion: Both treatment protocols resulted in significant improvements in the clinical and immunological parameters. When combined mechanical and antimicrobial protocol is desired and microbial cultures are not available, the use of both antibiotic regimens is recommended; the treatment of choice should be based on compliance, allergies, and potential side effects. Keywords: aggressive periodontitis, antibiotic regimen, clinical attachment level, cytokines, gingival crevicular fluid, treatment