This randomized, double-blind clinical trial assessed the clinical and microbiological effects of systemic azithromycin (AZ) as an adjunct to one-stage full-mouth disinfection (OSFMD) in patients with moderate to severe chronic periodontitis. Forty-two patients were assigned to OSFMD with either AZ or placebo. Clinical parameters and bacterial counts were evaluated at baseline, 90, and 180 days. Both groups showed significant reductions in probing pocket depth (PPD), attachment loss, bleeding, and plaque scores over time; however, no statistically significant intergroup differences were observed in clinical outcomes (p > 0.05). In contrast, the AZ group showed a statistically significant reduction in total bacterial counts and specific periodontopathogens (p < 0.05). Oral health-related quality of life (OHQOL) improved significantly in both groups 2 weeks post-treatment. Although AZ provided enhanced microbiological benefits, its adjunctive use did not yield additional clinical improvements. These findings suggest that routine use of AZ may not be justified for all patients undergoing OSFMD, though benefits may exist for selected high-risk cases.