Unfortunately, leprosy (Hansen's Disease) is very slow moving, taking years before fingers and noses fall off.  Also, it is treatable and has a very high cure rate.  Ebola or hemorrhagic fever although scary, are treatable with low kill rates.  Now, here is what are scary, but rare: Disease	                                 Treatment	CFR Transmissible spongiform encephalopathies	Currently Incurable	100% African trypanosomiasis	                        Untreated	      ~ 100% Visceral leishmaniasis.                         Incurable.              100% Visceral leishmaniasis AKA Kala Azar is 100% fatal, but takes a few weeks to months to kill. Best candidate for a huge die-off: Bubonic Plague, a zoonotic disease spread by fleas via vermin carriers such as rats.  It kills within a few days unless "heroic medical intervention" is taken.  There is no cure, but a partially effective vaccine (which has its own very unpleasant side effects). The Ultimate is Weaponized smallpox -- well, we won't even go there.  Goodnight Mrs. Calabash, wherever you are.