Chlamydia trachomatis was isolated from 9 of 19 men with acute, nondiarrheal Reiter's syndrome who had not recently taken antibiotics. None of 8 untreated men with other forms of arthritis were infected with this organism. Chlamydia trachomatis-specific antibody titers and cellular immune responses were positive significantly more often in 35 treated and untreated men with acute, nondiarrheal Reiter's syndrome than in 7 men with diarrhea-associated Reiter's syndrome and 8 men with other forms of arthritis. Mean peak chlamydial antibody titers and mean lymphocyte transformation stimulation indices were significantly higher in C. trachomatis-infected men with Reiter's syndrome than in C. trachomatis-infected men with uncomplicated nongonococcal urethritis. We concluded that C. trachomatis is capable of "triggering" Reiter's syndrome in susceptible men and that an exaggerated immune response to this organism may play a role in the pathogenesis of the disease.