Mouse models have indicated that the pneumococcal polysaccharide vaccine (PPV) can reduce atherosclerosis. This is probably through a process of molecular mimicry, where phosphorylcholine in the capsular polysaccharide of the vaccine elicits antibodies that cross-react with oxidised low-density lipoprotein and reduce plaque. We investigated whether a similar mechanism occurs in humans. A large national blinded, randomised, placebo-controlled trial of the PPV (Australian Study for the Prevention through Immunisation of Cardiovascular Events [AUSPICE]) is underway with fatal and nonfatal cardiovascular disease (CVD) events as the primary outcome. Participants at one centre agreed to a substudy measuring a number of biomarkers and surrogates of CVD over 4 years, including anti-pneumococcal antibodies (immunoglobulin G and immunoglobulin M), C-reactive protein, carotid intima-media thickness, pulse wave velocity, insulin, fasting blood glucose, glycated haemoglobin, and hepatorenal index. Antipneumococcal immunoglobulin G and immunoglobulin M were both present and statistically significantly increased in the treated group compared to control at 4 years. However, there were no differences in any of the surrogate measures of CVD or metabolic markers at 4 years. While there were prolonged differences in anti-pneumococcal antibody titres following PPV vaccination, these did not appear to provide any cardioprotective effect, as measured by a range of markers. Final results using the fatal and nonfatal CVD events await the completion of national health record linkage next year. ACTRN12615000536561.