The Key Largo cotton mouse is the largest of all subspecies of cotton mouse found in peninsular Florida (U.S. Fish & Wildlife Service, 1999).  This cotton mouse subspecies can reach a body length of seven inches (17.9 centimeters) with a tail length of three inches (7.7 centimeters).  Key Largo cotton mice have a dark hazel back with reddish brown sides, a white belly, white feet, and a tail that is brown on top and white on the bottom.

Habitat loss and fragmentation have isolated populations of the Key Largo cotton mouse, which increases the severity of all other threats.  Isolated populations have reduced gene flow which leads to lower genetic diversity, and potentially lower survival.  Fragmentation along its small range also makes the Key Largo cotton mouse vulnerable to tropical storms and hurricanes.  Trash dumping (a result of increased urbanization) also threatens the Key Largo cotton mouse, leading to an increased population of black rats (Rattus rattus).  Black rats may out-compete the Key Largo cotton mouse for food and other resources.  Sea level rise is an impending threat to the Key Largo cotton mouse population.