Aims: Many countries reported an increase of out-of-hospital cardiac arrests (OHCAs) and mortality during the COVID-19 pandemic. However, all these data refer to regional settings and national data are still missing. We aimed to assess the OHCA incidence and population mortality during COVID-19 pandemic in whole Switzerland and in the different regions (Cantons) according to the infection rate. Methods: We considered OHCAs and deaths which occurred in Switzerland after the first diagnosed case of COVID-19 (February 25th) and for the subsequent 65 days and in the same period in 2019. We also compared Cantons with high versus low COVID-19 incidence. Results: A 2.4% reduction in OHCA cases was observed in Switzerland. The reduction was particularly high (-21.4%) in high-incidence COVID-19 cantons, whilst OHCAs increased by 7.7% in low-incidence COVID-19 cantons. Mortality increased by 8.6% in the entire nation: a 27.8% increase in high-incidence cantons and a slight decrease (-0.7%) in low-incidence cantons was observed. The OHCA occurred more frequently at home, CPR and AED use by bystander were less frequent during the pandemic. Conversely, the OHCAs percentage in which a first responder was present, initiated the CPR and used an AED, increased. The outcome of patients in COVID-19 high-incidence cantons was worse compared to low-incidence cantons. Conclusions: During the COVID-19 pandemic in Switzerland mortality increased in Cantons with high-incidence of infection, whilst not in the low-incidence ones. OHCA occurrence followed an opposite trend showing how variables related to the health-system and EMS organization deeply influence OHCA occurrence during a pandemic.