Rabbit hemorrhagic disease, a notifiable foreign animal disease in the USA, was reported for the first time in wild native North American rabbits and hares in April 2020 in the southwestern USA. Affected species included the Desert Cottontail (Sylvilagus audubonii), Mountain Cottontail (S. nutallii), Black-tailed Jackrabbit (Lepus californicus), and Antelope Jackrabbit (L. alleni). Desert Cottontails (n=7) and Black-tailed Jackrabbits (n=7) collected in April and May 2020 were necropsied at the U.S. Geological Survey National Wildlife Health Center (NWHC) and tested positive for Lagovirus europaeus GI.2, also known as rabbit hemorrhagic disease virus 2 (GI.2/RHDV2/b), by real-time PCR at the U.S. Department of Agriculture’s Foreign Animal Disease Diagnostic Laboratory. Gross and microscopic lesions were similar to those reported in European rabbits (Oryctolagus cuniculus) and other hare (Lepus) species with GI.2/RHDV2/b infection and included epistaxis (12/13; 92%), massive hepatocellular dissociation (14/14; 100%) and necrosis/apoptosis (11/11; 100%), pulmonary congestion (12/12; 100%), edema (12/13; 92%), and hemorrhage (11/12; 92%), and acute renal tubular injury (3/8; 38%). As in previous reports and when compared to historical cases in the NWHC diagnostic database, massive hepatocellular dissociation and necrosis/apoptosis was the most diagnostically distinct finding in GI.2/RHDV2/b-positive rabbits and hares. Based on the apparent susceptibility of North American Sylvilagus and Lepus species to fatal GI.2/RHDV2/b infection, additional work is needed to understand the host range, pathogenicity, and potential population impacts of GI.2/RHDV2/b in North America.