H. capsulatum groups with B. dermatitidis and the South American pathogen Paracoccidioides brasiliensis in the recently recognized fungal family Ajellomycetaceae.

The great majority of North American isolates belongs to a single genetic type,[5][6] but a study of multiple genes suggests a recombining, sexual population.

The enzootic and endemic zones of H. capsulatum can be roughly divided into core areas, where the fungus occurs widely in soil or on vegetation contaminated by bird droppings or equivalent organic inputs, and peripheral areas, where the fungus occurs relatively rarely in association with soil, but is still found abundantly in heavy accumulations of bat or bird guano in enclosed spaces such as caves, buildings, and hollow trees.

[7][8][9] In some areas, such as Kansas City, skin testing with the histoplasmin antigen preparation shows that 80–90% of the resident population have an antibody reaction to H. capsulatum, probably indicating prior subclinical infection.

[7] Northern U.S. states such as Minnesota, Michigan, New York and Vermont are peripheral areas for histoplasmosis, but have scattered counties where 5–19% of lifetime residents show exposure to H. capsulatum.

The St. Lawrence Valley is probably the best known endemic region based both on case reports and on a number of skin test reaction studies that were done between 1945 and 1970.

[12][13][14][15][16] Exposure of aboriginal Canadians occurs remarkably far north in Quebec,[17][18] but has not been reported in similar boreal biogeoclimatic zones in many other parts of Canada.

Recently and remarkably, a cluster of four indigenously acquired cases of histoplasmosis was shown to be associated with a golf course in suburban Edmonton, Alberta.

The organism tends to remain alive in the scattered pulmonary calcifications; therefore, some cases are detected by emergence of serious infection when a patient becomes immunocompromised, perhaps decades later.

Emphysema sufferers may contract chronic cavitary pulmonary histoplasmosis as a disease complication; eventually the cavity formed may be occupied by an Aspergillus fungus ball (aspergilloma), potentially leading to massive hemoptysis.

[20] Another uncommon form of histoplasmosis is a slowly progressing condition known as granulomatous mediastinitis, in which the lymph nodes in the mediastinal cavity between the lungs become inflamed and ultimately necrotic; the swollen nodes or draining fluid may ultimately affect the bronchi, the superior vena cava, the esophagus or the pericardium.

[7][22] Histoplasmosis outbreaks are typically associated with cleaning guano accumulations or clearing guano-covered vegetation, or with exploration of bat caves.

[24] As with blastomycosis, a good understanding of the precise ecological affinities of H. capsulatum is greatly complicated by the difficulty of isolating the fungus directly from nature.

[27] In 1905, Samuel Taylor Darling serendipitously identified a protozoan-like microorganism in an autopsy specimen while trying to understand malaria, which was prevalent during the construction of the Panama Canal.