This study aimed to study the association between shift work and incident and fatal cardiovascular disease (CVD), and to explore modifying and mediating factors.

This is a population-based, prospective cohort study with a median follow-up of 11 years; 238 661 UK Biobank participants who were in paid employment or self-employed at baseline assessment were included.

Shift workers had higher risk of incident [hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.06–1.19] and fatal (HR 1.25, 95% CI 1.08–1.44) CVD compared with non-shift workers, after adjusting for socio-economic and work-related factors. The risk was higher with longer duration of shift work, in women and in jobs with little heavy manual labour. Current smoking, short sleep duration, poor sleep quality, adiposity, higher glycated haemoglobin and higher cystatin C were identified as the main potentially modifiable mediators. Mediators collectively explained 52.3% of the associations between shift work and incident CVDs.

Shift workers have higher risk of incident and fatal CVD, partly mediated through modifiable risk factors such as smoking, sleep duration and quality, adiposity and metabolic status. Workplace interventions targeting these mediators have the potential to alleviate shift workers’ CVD risk.