Although the histopathologic changes associated with Cyclospora cayetanensis infection have been previously described, the histopathology and the appearance of various life cycle stages have not been correlated with severity, stage, and duration of clinical disease. We report a prospective clinical investigation of disease characteristics and histopathologic findings in three otherwise healthy, immunocompetent patients with symptomatic C. cayetanensis infection, the duration of which ranged from 6 to 60 days. Varying degrees of gross and microscopic gastrointestinal inflammation were seen before treatment. An electron-dense phospholipid membrane/myelin-like material was variably present both before and after treatment. The greatest amount of myelin-like material was seen in the patient with prolonged disease. The results of our study suggest that inflammatory changes associated with C. cayetanensis infection may persist beyond parasite eradication. It is intriguing to speculate that the myelin-like material is a marker for persistent inflammation, but further study and confirmation are needed.