Granulomatous uveitis induced by Mycobacterium tuberculosis infection has been less frequently encountered over the last 20 years. Differential diagnosis of M. tuberculosis and other atypical mycobacteria is nevertheless of particular interest in patients with acquired immune deficiency syndromes. We present the case of a 60-year-old man who was referred to our clinic because of therapy-refractive endophthalmitis. Diagnostic vitrectomy including microbiological examination as well as further extensive serological examinations did not reveal any further information on the etiology. Despite intensive anti-inflammatory treatment, the eye became blind and developed secondary glaucoma. Evisceration of the globe had to be performed. Histopathological examination showed a granulomatous inflammation without the tuberculosis-typical development of central caseous necrosis. Further molecular pathological investigations had to be performed with regard to differential diagnostic aspects. By means of the polymerase chain reaction we could detect mycobacterial gene sequences that corresponded to atypical mycobacteria. The diagnosis of atypical mycobacterial infection was confirmed Molecular-genetics examination techniques, especially those involving the polymerase chain reaction, will become more important in routine histopathological examination. These techniques can be performed on paraffin-fixed or formalin-embedded material for further differential diagnostic considerations.