No prospective studies exist on the relationship between change in periodontal clinical and microbiological status and progression of carotid atherosclerosis. The Oral Infections and Vascular Disease Epidemiology Study examined 420 participants at baseline (68 ± 8 years old) and follow-up. Over a 3-year median follow-up time, clinical probing depth (PD) measurements were made at 75 766 periodontal sites, and 5008 subgingival samples were collected from dentate participants (average of 7 samples/subject per visit over 2 visits) and quantitatively assessed for 11 known periodontal bacterial species by DNA-DNA checkerboard hybridization. Common carotid artery intima-medial thickness (CCA-IMT) was measured using high-resolution ultrasound. In 2 separate analyses, change in periodontal status (follow-up to baseline), defined as (1) longitudinal change in the extent of sites with a ≥ 3-mm probing depth (Δ%PD ≥ 3) and (2) longitudinal change in the relative predominance of bacteria causative of periodontal disease over other bacteria in the subgingival plaque (Δetiologic dominance), was regressed on longitudinal CCA-IMT progression adjusting for age, sex, race/ethnicity, diabetes, smoking status, education, body mass index, systolic blood pressure, and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Mean (SE) CCA-IMT increased during follow-up by 0.139 ± 0.008 mm. Longitudinal IMT progression attenuated with improvement in clinical or microbial periodontal status. Mean CCA-IMT progression varied inversely across quartiles of longitudinal improvement in clinical periodontal status (Δ%PD ≥ 3) by 0.18 (0.02), 0.16 (0.01), 0.14 (0.01), and 0.07 (0.01) mm (P for trend<0.0001). Likewise, mean CCA-IMT increased by 0.20 (0.02), 0.18 (0.02), 0.15 (0.02), and 0.12 (0.02) mm (P<0.0001) across quartiles of longitudinal improvement in periodontal microbial status (Δetiologic dominance). Longitudinal improvement in clinical and microbial periodontal status is related to a decreased rate of carotid artery IMT progression at 3-year average follow-up.