Ingestion of wild and potentially toxic mushrooms is common in the United States and many other parts of the world. US poison centers have been logging cases of mushroom exposure in The National Poison Data System (NPDS) annual publications for over 30 years. This study compiles and analyzes US mushroom exposures as reported by the NPDS from 1999 to 2016. Over the last 18 years, 133 700 cases (7428/year) of mushroom exposure, mostly by ingestion, have been reported. Cases are most frequently unintentional (83%, P < 0.001); cause no or only minor harm (86%, P < 0.001); and in children <6 years old (62%, P < 0.001). Approximately 704 (39/year) exposures have resulted in major harm. Fifty-two (2.9/year) fatalities have been reported, mostly from cyclopeptide (68-89%)-producing mushrooms ingested by older adults unintentionally. The vast majority of reported ingestions resulted in no or minor harm, although some groups of mushroom toxins or irritants, such as cyclopepides, ibotenic acid, and monomethylhydrazine, have been deadly. Misidentification of edible mushroom species appears to be the most common cause and may be preventable through education.