Recent evidence suggests that lizards of the family Chamaeleonidae are one of the most heavily parasitized groups of reptiles kept in captivity; however, little is known about the clinical implications of these infections. Relative to other host species, there is a paucity of information on reptile parasites and the breadth of parasites that infect chameleons is not well described. We report a parasitic infection most consistent with organisms belonging to the Mesomycetozoea group in male and female wild-caught jeweled chameleons (Furcifer campani). Clinical features of infection included persistent weight loss, despite increased food intake; cachexia; abnormally increased light- and heat-seeking behavior; coelomic distention; and loose, watery stools. Histologically, there was extensive granuloma formation present in the liver and widespread localization of periodic acid–Schiff- and Grocott's methenamine silver–positive spores resembling those of Dermocystidium sp. in the bone marrow, gastrointestinal tract, and other tissues. A second case of infection with this pathogen also presented with concurrent Mycobacterium sp. throughout the body, suggesting that infection with mesomycetozoean organisms may serve as a primary cause of death, or conversely, may render the infected individual susceptible to secondary, opportunistic infection. The rapid health decline associated with infection in these cases indicates a need to better characterize prevalence and pathogenicity of parasites in captive chameleons.