A retrospective study was performed by reviewing all Heloderma spp. submissions to Northwest ZooPath from 1996 to 2019. Necropsy and biopsy specimens from 106 captive Gila monsters (Heloderma suspectum) and 49 captive beaded lizards (Heloderma horridum) were reviewed. Inflammatory diseases were the most frequently diagnosed condition in Heloderma spp., and were diagnosed in 72% of all animals examined, including 76% of Gila monsters and 63% of beaded lizards. The most common cause of inflammation was bacterial infection, which was present in 52% of all Heloderma spp. with inflammation. Enterocolitis was common in Gila monsters (20%) and beaded lizards (14%), but the underlying causes were different for each species. Cryptosporidium spp. was the most common cause of enterocolitis in Gila monsters (36%) but was not identified in beaded lizards. Amoebiasis was a common cause of enterocolitis in Gila monsters (27%) and was the most common cause of enterocolitis in beaded lizards (57%). Deposition diseases were diagnosed in 34% of all Heloderma spp. The most frequently diagnosed deposition disease in beaded lizards was urolithiasis-nephrolithiasis (12%). This disease was not diagnosed in Gila monsters. Deposition diseases that were common in Gila monsters and beaded lizards included hepatic lipidosis and renal gout. Neoplasia was diagnosed in 17% of all Heloderma spp., including 17% of Gila monsters and 18% of beaded lizards. The most common neoplasm of Heloderma spp. was renal adenocarcinoma, which was equally common in Gila monsters and beaded lizards. Less common diagnoses included degenerative diseases, trauma, nutritional disease, nonneoplastic proliferative disease, nondegenerative cardiovascular disease, and congenital malformation.