Sudden cardiac death (SCD) is the leading cause of death. The current paradigm in SCD requires the presence of an abnormal myocardial substrate and an internal or external transient factor that triggers cardiac arrest. Based on prior mechanistic evidence, we hypothesized that an unusually cold weather event (a cold spell) could act as an external factor triggering SCD. We tested potential effect modification of prior diagnoses and select pharmacological agents disrupting pathological pathways between cold exposure and death. The home coordinates of 2572 autopsy-verified cases of ischaemic SCD aged ≥35 in the Province of Oulu, Finland, were linked to 51 years of home-specific weather data. Based on conditional logistic regression, an increased risk of ischaemic SCD associated with a cold spell preceding death (OR 1.49; 95% CI: 1.06-2.09). Cases without a prior diagnosis of ischaemic heart disease seemed more susceptible to the effects of cold spells (OR 1.70; 95% CI: 1.13-2.56) than cases who had been diagnosed during lifetime (OR 1.14; 95% CI: 0.61-2.10). The use of aspirin, β-blockers, and/or nitrates, independently and in combinations decreased the risk of ischaemic SCD during cold spells. The findings open up new lines of research in mitigating the adverse health effects of weather.