Yellow fever is a viral infection transmitted by mosquitoes. In the initial stages the victim suffers headache, muscle aches, fever, loss of appetite, vomiting, jaundice, kidney failure, and bleeding. Those who do not recover from this stage can then experience multi-organ dysfunction including liver and kidney failure, brain dysfunction, seizures, coma, shock, and death. Yellow fever gets its name from the jaundice that affects many patients, causing yellow eyes and yellow skin.
 
The 1867 yellow fever epidemic at Fort Jefferson was part of a wider yellow fever epidemic that killed thousands of people along the gulf coast from Texas to Florida, and northward up the Mississippi valley to Memphis, Tennessee. At Fort Jefferson, the epidemic began on August 18, 1867 when a soldier in Company K was felled with the disease. On the 20th, a second Company K soldier was stricken, and on the 21st two more were stricken. 

 On August 22nd, Private James Forsythe, 5th U.S. Artillery, was the first to die. Private Joseph Enits died next, on August 30th. The fever spread to Company L and to the officers’ servants. Company I, housed in the barracks adjoining the hospital, was then attacked. Company M escaped the plague until September 7th when 30 men were stricken.

The prison doctor, Brevet Major Joseph Sim Smith, an 1858 graduate of Georgetown University Medical School, contracted the disease on September 5th. Dr. Mudd then volunteered to take over caring for the sick until a replacement for Dr. Smith arrived, and the commanding officer, Major Valentine H. Stone, agreed. 

Dr. Smith died on September 8th. The next day, Smith was replaced by 60 year-old Dr. Daniel W. Whitehurst from Key West. For the next two months, Drs. Mudd and Whitehurst worked day and night to treat those afflicted with yellow fever, which included nearly everyone at the fort, soldiers and prisoners alike. Samuel Arnold and Michael O’Laughlen both contracted the disease. Arnold survived, but O’Laughlen died on September 23rd. Dr. Mudd himself contracted the disease on October 4th, forty-seven days after the epidemic had begun.

By the end of October, the yellow fever epidemic had begun to abate. The last case occurred on November 14th. Dr. Thomas, the new physician who had replaced Dr. Whitehurst, came down with the fever himself. Dr. Mudd, although not fully recovered, resumed caring for the remaining sick. When it was all over, 270 of the 400 people at the fort had caught yellow fever, and 38 had died, including Michael O'Laughlen. 

Dr. Mudd recounted the story of the yellow fever epidemic in a long letter to his wife on October 27, 1867.

Surviving Fort Jefferson soldiers signed a petition asking the government to release Dr. Mudd in recognition of his services in saving so many lives during the course of the epidemic. But President Johnson ignored the petition for Dr. Mudd’s release. He was still under political siege in Washington. In his 1869 pardon, a year and a half after the epidemic, Johnson mentioned Dr. Mudd’s work during the epidemic, but it was only one of several reasons given for the pardon.