Abstract Background Living in a greener neighbourhood may reduce the risk of developing incident cardiovascular disease, but evidence is limited by reliance on cross-sectional comparisons. We use data from a longitudinal study with a time-independent measure of risk to explore the association between exposure to greenspace and cardiovascular disease. Methods Data was from the European Prospective Investigation of Cancer Norfolk UK cohort, baseline 1993-1997 (n=24,420). Neighbourhoods were defined as 800m radius zones around participants’ home, according to their home postcode (zip code) in the year 2000. Greenspace exposure was identified using classified satellite imagery. Adjusted Cox proportional hazards regression examined associations between greenspace and incident cardiovascular disease. Mediation analysis assessed if physical activity mediated associations, whilst modification by rurality, socio-economic status and age was explored. Results The mean age of participants was 59.2 years at baseline, 54.7% were female, and mean follow-up time was 14.5 years. Individuals living in the greenest neighbourhood quartile had a 7% lower relative hazard of developing cardiovascular disease than other neighbourhoods (HR 0.93; 95% CI 0.88, 0.97; p=0.003) after adjusting for age, sex, BMI, prevalent diabetes and socio-economic status (SES). Physical activity did not mediate the relationship (greenest compared to the least green quartile HR 0.99; 95% CI 0.97, 1.01; p=0.416). Models predicted incidence of cardiovascular disease in the least green neighbourhoods (19.4% greenspace on average) would fall by 4.8% (95% CI 1.6%, 8.2% p=0.003) if they were as green as the average neighbourhood (59.0% greenspace). Occupation moderated the relationship, whereby exposure to greenspace was not associated with incident CVD for participants engaged in manual occupations. Conclusions Greener home neighbourhoods may protect against risk of cardiovascular disease even after accounting for SES, whilst the mechanism does not appear to be strongly associated with physical activity. Putative causal mechanisms require investigation.