This is the first report of localized tendosynovial human protothecosis in an HIV-positive host. The lesion appeared as a nodule in the extensor face of the thumb. A simple excision was performed, and histology confirmed numerous granulomas, some with central fibrinoid necrosis. Enormous numbers of prototheca were found in periodic acid-Schiff and Gömöri methenamine silver stains, evidencing endosporulation with diagnostic morula- or daisy-like sporangia. The presence of prototheca species was confirmed by direct immunofluorescence with the specific conjugate. The cellular response estimated by the relative number of polymorphonuclear leukocytes, lymphocytes, and plasma cells was minimal, although granuloma formation was unaffected. The infective agents were found either extracellularly or harbored by macrophages and giant cells.