Pada 19 Mac 2021, diumumkan bahawa De KlerKlerk telah didiagnosis dengan penyakit [[Mesothelioma]].<ref>{{Cite web |url=https://www.iol.co.za/news/south-africa/fw-de-klerk-diagnosed-with-cancer-undergoes-treatment-b085e48a-895e-42ba-817b-1d20b3a61d3c |first=Lee |last=Rondganger |date=19 March 2021 |title=FW de Klerk diagnosed with cancer, undergoes treatment |website=[[Independent Online (Afrika Selatan)|Independent Online]] |language=en |access-date=11 November 2021 |archive-date=11 November 2021 |archive-url=https://web.archive.org/web/20211111174057/https://www.iol.co.za/news/south-africa/fw-de-klerk-diagnosed-with-cancer-undergoes-treatment-b085e48a-895e-42ba-817b-1d20b3a61d3c |url-status=live }}</ref> Beberapa bulan kemudian, pada 11 November, beliau meninggal akibat komplikasi dari penyakit itu di rumahnya di [[Cape Town]], pada usia 85 tahun.<ref name="kematian-astro">{{cite news|url=https://www.astroawani.com/berita-dunia/bekas-presiden-afrika-selatan-fw-de-klerk-meninggal-dunia-330415|title=Bekas Presiden Afrika Selatan, FW de Klerk meninggal dunia|first=Nickyson|last=Nyambar|work=[[Astro Awani]]|date=11 November 2021|access-date=18 November 2021=url-status=live}}</ref><ref>{{Cite news|last=Lacey|first=Marc|date=11 November 2021|title=F.W. de Klerk, Last President of Apartheid South Africa, Dies at 85|language=en-US|work=The New York Times|url=https://www.nytimes.com/2021/11/11/world/africa/fw-de-klerk-dead.html|access-date=11 November 2021|issn=0362-4331|archive-date=11 November 2021|archive-url=https://web.archive.org/web/20211111105004/https://www.nytimes.com/2021/11/11/world/africa/fw-de-klerk-dead.html|url-status=live}}</ref><ref>{{Cite news|title=F.W. de Klerk, South African Nobel Prize winner for opening government, dies at 85|language=en-US|work=The Washington Post|url=https://www.washingtonpost.com/local/obituaries/fw-deklerk-death-south-africa/2021/11/11/761faa64-8fd4-11e6-a6a3-d50061aa9fae_story.html|date=11 November 2021|first=Glenn|last=Frankel|access-date=11 November 2021|issn=0190-8286|archive-date=11 November 2021|archive-url=https://web.archive.org/web/20211111105308/https://www.washingtonpost.com/local/obituaries/fw-deklerk-death-south-africa/2021/11/11/761faa64-8fd4-11e6-a6a3-d50061aa9fae_story.html|url-status=live}}</ref>
