Carotid intima-media thickness (cIMT) is a valid measure of cardiovascular disease (CVD). Physical activity appears to improve cIMT, however, research is inconclusive. This study investigated the relationship between physical activity (physical activity rating (PA-R)) and cardiovascular fitness (predicted VO2max , perceived functional ability (PFA)) and cIMT. Data collected from 341 seniors (≥50 years) competing in the Huntsman World Senior Games (HWSG) included blood lipids, inflammatory makers, blood glucose, blood pressure (BP) and anthropometric measurements of obesity and central adiposity. Multiple regression analysis was used to determine correlations of measured variables with cIMT. Two of the fitness related variables, PFA (r ≈ 0.1359; p = 0.012) and predicted VO2max (r ≈ 0.1475; p = 0.007) were significantly correlated to cIMT without controlling for confounding factors, but lost significance when adjustments for other CVD risk factors were included. PAR (r ≈ 0.0869; p = 0.111) was not significantly correlated to cIMT. Regression analysis indicated that the most predictive variables of cIMT we investigate were: age (t = 7.166, p = 0.000), gender (t = 3.310, p = 0.001), BMI (t = 1.892, p = 0.05), SBP (t = 3.952, p = 0.000), total cholesterol (TC) (t = 4.184, p = 0.000) and triglycerides (TRG) (t ≈ 3.466, p = 0.000), our R2 = .299, thus indicating these 6 variables account for about 30% of the variance in cIMT in seniors competing at HWSG. Physical activity and cardiovascular fitness influence other CVD risk factors and consequently may have an indirect impact on cIMT.