Introduction – This study describes cause-specific mortality in 2021, a year in which SARS-CoV-2 infection was still prevalent in France, by comparing its trends with those observed between 2015 and 2019 and in 2020. Methods – Using death certificates for residents who died in France in 2021, as well as between 2015 and 2020, the medical causes of death were coded according to the World Health Organization’s (WHO) International Classification of Diseases, 10th Revision (ICD-10). The underlying causes of death were grouped according to the European list of causes of death, to which COVID-19 was added. The number of deaths and age-standardized mortality rates were analyzed by cause, age group, and sex. The rates for 2020 and 2021 are compared to trend-adjusted mortality levels estimated using a Poisson regression model between 2015 and 2019. Results – COVID-19 remains the third leading cause of death behind neoplasms and diseases of the circulatory system, with victims younger than in 2020. The pandemic had a significant impact on the overseas departments and regions (DROM). Increases in mortality due to circulatory system diseases were observed in 2021, and for endocrine, nutritional, and metabolic diseases as well as digestive system diseases starting in 2020, compared to trends from 2015–2019. Discussion – The deviations from past trends are consistent with international findings and help document the possible direct and indirect effects of the COVID-19 pandemic on mortality.