During the first COVID-19 wave in Switzerland, relative mortality was at least eight times higher compared with the uninfected general population. We aimed to assess sex-specific and age-specific relative mortality associated with a SARS-CoV-2 diagnosis during the second wave. Prospective population-based study. Individuals testing positive for SARS-CoV-2 after the start of the second wave on 1 October 2020 were followed up until death or administrative censoring on 31 December 2020. 5 179 740 inhabitants of Switzerland in fall 2018 aged 35-95 years (without COVID-19) and 257 288 persons tested positive for SARS-CoV-2 by PCR or antigen testing during the second wave. The planned outcome measure was time to death from any cause, measured from the date of a SARS-CoV-2 diagnosis or 1 October in the general population. Information on confirmed SARS-CoV-2 diagnoses and deaths was matched by calendar time with the all-cause mortality of the general Swiss population of 2018. Proportional hazards models were used to estimate sex-specific and age-specific mortality rates and probabilities of death within 60 days. The risk of death for individuals tested positive for SARS-CoV-2 in the second wave in Switzerland increased at least sixfold compared with the general population. HRs, reflecting the risk attributable to a SARS-CoV-2 infection, were higher for men (1.40, 95% CI 1.29 to 1.52) and increased for each additional year of age (1.01, 95% CI 1.01 to 1.02). COVID-19 mortality was reduced by at least 20% compared with the first wave in spring 2020. General mortality patterns, increased for men and older persons, were similar in spring and in fall. Absolute and relative COVID-19 mortality was smaller in fall. The protocol for this study was registered on 3 December 2020 at https://osf.io/gbd6r. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.