The survey methodology for the 2021 Santé publique France Barometer is based on the random generation of landline and mobile phone numbers. The survey population includes individuals aged 18 to 85 who reside in metropolitan France and speak French. The survey was conducted by telephone by the Ipsos Institute. It began on February 11, 2021, and ended on December 15, 2021. A total of 24,514 people aged 18 to 85, residing in metropolitan France and speaking French, participated. Seven out of ten interviews were conducted following the random selection of a mobile phone number, and three out of ten following the selection of a landline number. The response rate was 44.3%, with the questionnaire taking an average of 36 minutes to complete. This thirteenth edition of the Santé publique France Barometer was designed primarily to produce regional estimates for topics historically tracked in the Barometer (addictions, vaccination, nutrition). The large sample size planned for this purpose (24,514 people aged 18 to 85) was also intended to enable the production of estimates and interpretive insights on localized issues (such as pesticides, for example), rare events (such as suicidal behavior or musculoskeletal disorders), or specific populations (such as pregnant women or parents of young children). This edition also provided an opportunity to assess the health status of the French population after a year of the pandemic, particularly to take stock of the population’s mental health and to gather information on the settings where COVID-19 transmission occurred.