BACKGROUND The natural history of flock worker's lung (FWL) and longitudinal lung function changes in nylon flock-exposed workers have not been well characterized. METHODS Symptoms, pulmonary function testing, and chest radiographs from five index cases, subsequent case referrals, and screened employees of a flocking plant in Kingston, Ontario, Canada, were compared and analyzed for changes over time (variable follow-up intervals between 1991 and 2011). RESULTS Nine cases and 30 flock-exposed workers without FWL were identified. Four cases had persistent interstitial lung disease despite three having left the workplace. Two developed hypoxemic respiratory failure and secondary pulmonary hypertension and died of complications 18 and 20 years after diagnosis, respectively. Five cases resolved after leaving the workplace. Compared with resolved cases, persistent cases had lower diffusing capacity of the lung for carbon monoxide at presentation (P < .05) and follow-up (P < .05). Among exposed workers employed for 14.5 ± 4.7 years, five had abnormal chest radiographs vs none at baseline (P = .001) over 14.8 ± 4.6 years of follow-up. The prevalence of wheeze increased (P = .001), and FEV₁/FVC decreased (P < .001). FEV₁% predicted was significantly lower at follow-up (P = .05). Average FEV₁ decline was 46 mL/year (range, -27 to 151 mL/y). Seventy-seven percent of exposed workers were current or former smokers. CONCLUSIONS The natural history of FWL includes the following patterns: complete resolution of symptoms; radiographic and pulmonary function abnormalities; permanent, but stable symptoms and restrictive pulmonary function deficits; and progressive decline in pulmonary function, causing death from respiratory failure and secondary pulmonary hypertension. A low baseline diffusing capacity of the lung for carbon monoxide is associated with the persistence and progression of FWL.