A unique cluster of three cases of sarcoidosis developed recently among 10 white firefighters who trained together as apprentices in 1979. This led us to hypothesize that firefighters are at increased risk of this condition because of the combined effect of smoke exposure and infection with a communicable agent, such as Chlamydia pneumoniae, a recently proposed cause of sarcoidosis. We conducted a case-finding questionnaire survey of 1,282 active and retired male Providence firefighters and police officers and then evaluated both the index apprenticeship class and two control cohorts by chest radiography, seromarkers of T lymphocyte activation (neopterin and sIL-2R), and chlamydial serology. One additional case of sarcoidosis was identified among the 990 (77%) survey respondents. No new cases were detected in the subsequent laboratory investigation of 46 (87%) firefighters from the index 1979 apprenticeship class, 53 (75%) firefighter controls from the 1974 and 1980 classes, or 50 (30%) police officer controls from 1973–1981 classes. The cohorts did not differ with regard to either C. pneumoniae antibody titers or sIL-2R levels, but serum neopterin was elevated (> 9.0 nmol/L) in 20% (eight of 41) of the index cohort, 22% (11 of 51) of firefighter controls, and 4% (two of 48) of police officers. Logistic regression found firefighting to be the only significant predictor of neopterin elevation (odds ratio 5.8; 95% CI, 1.3 to 26.9). Our results suggest that firefighters may be at risk of T lymphocyte activation. Determining whether this reflects an enhanced risk of lymphocytic alveolitis and whether firefighters are more likely to develop sarcoidosis requires further study.