An epidemic often provides an opportunity to obtain evidence of the etiologic association of a microorganism with disease. Chlamydia pneumoniae TWAR is a newly recognized organism whose relationship to disease is not completely understood. An outbreak of C. pneumoniae infections from November 1990 to February 1991 was studied in University of Washington students. Twelve TWAR infections were identified serologically in 54 students with acute respiratory disease. The organism was isolated from 7 of the 12 and identified by the polymerase chain reaction (PCR) in 2 that were isolation-negative. The organism was not found in any of the 42 serologically negative patients or in 51 control student patients without respiratory illness cultured in 1991. There was no evidence of infection with Mycoplasma pneumoniae or respiratory viruses in the 12 patients with C. pneumoniae infection. During the 4-month outbreak, there was an increase in total pneumonia cases. These findings provide evidence for an etiologic association of C. pneumoniae with pneumonia and bronchitis.