Background Shift work has been associated with an increased risk of cardiovascular disease (CVD). However, there is a need for more studies to determine whether there is an interaction between shift work and other risk factors of CVD, thereby increasing the risk of CVD in shift workers. Aims To discern whether shift work and parental mortality from myocardial infarction (MI) or sudden cardiac death (SCD) interact to increase the risk of MI in men. Methods A case-control dataset was used to assess interaction between shift work and parental history of CVD, using death from MI or SCD, or death before age 65, on an additive scale. Results were reported as relative excess risk due to interaction, attributable proportion due to interaction (AP) and synergy index (SI). Results There was an interaction between shift work and paternal mortality from MI or SCD, when both factors were present [SI = 2.39; 95% confidence interval (CI) 1.02. 5.6 and AP = 0.4; 95% CI 0.08. 0.73]. Conclusions Paternal mortality from MI or SCD interacts with shift work to increase the risk of MI in men.