Systemic antibiotics have been recommended for the treatment of destructive periodontal disease. Our goal was to relate antibiotic use for medical or dental reasons to subsequent tooth loss in a cohort of 12,631 persons with destructive periodontal disease. After adjustment for age, smoking, and other confounders, the dispensing of antibiotics for 1-13 days, 14-20 days, or 21 or more days was not associated with reduced tooth loss [Adjusted rate ratio (RR) = 1.0; 95% Confidence Interval (CI) = 0.8-1.1; RR = 1.2; 95% CI = 0.9-1.4, and RR =1.2, 95% CI =1.0-1.3, respectively]. Numerous subgroup analyses were consistent with these overall null findings, with two exceptions: Longer courses of tetracyclines were associated with reduced tooth loss among persons receiving periodontal care, and penicillin was associated with reduced tooth loss among persons with more severe disease. Long-term, larger randomized trials are needed to provide evidence that antibiotics reduce tooth loss when used in the management of destructive periodontal disease.