Sarcoidosis, of unknown etiology, may result from exposure of a genetically susceptible subject to a specific environmental agent(s), possibly an infectious one, although none has been identified. Propionibacterium acnes is so far the only bacterium to be isolated from sarcoid lesions. Genomes of P. acnes have been detected in large numbers in sarcoid lymph nodes by the quantitative polymerase chain reaction. By in situ hybridization, P. acnes genomes were found in sarcoid lymph nodes in and around sarcoid granulomas. These results point to an etiological link between P. acnes and some cases of sarcoidosis. Host factors may be more critical than agent factors in the etiology of sarcoidosis, as already suggested from the phenomenon of the Kveim test, in which a suspension of sarcoid tissues injected intracutaneously causes sarcoid granulomas in patients with sarcoidosis but not in healthy people or patients with other diseases. A recombinant trigger-factor protein, RP35, from P. acnes causes a cellular immune response in some patients with sarcoidosis, but not in subjects without sarcoidosis. RP35 caused pulmonary granulomas in mice sensitized with the protein and adjuvant. Sarcoid granulomas may form during hypersensitivity to antigens of P. acnes indigenous to or proliferating in the affected organ.