The explanations for the emergence of cryptogenic fibrosing alveolitis as a new clinical entity during the second half of the 20th century are unclear. The authors have previously reported evidence of an increased risk of cryptogenic fibrosing alveolitis in relation to the use of antidepressant drugs. The authors have now tested this hypothesis a priori in an analysis of computerized general practice records for 890 cases of cryptogenic fibrosing alveolitis and 5,884 matched controls drawn from the UK General Practice Research Database. Exposure to antidepressants at the time of diagnosis was increased in cases compared to controls (odds ratio (OR) 1.52, 95% confidence interval (95% CI) 1.24-1.86), and this increase remained if the analysis was restricted to exposures 4 yrs prior to diagnosis (OR 1.50, 95% CI 0.98-2.30). However this increased prescribing was not specific to any particular class of antidepressant or individual drug, and there was no evidence of a dose-response relationship between exposure to amitriptyline (the most commonly prescribed antidepressant) and disease. The presented data do not allow any firm conclusion to be made as to whether there is a causal relationship between antidepressant exposure and cryptogenic fibrosing alveolitis, but it seems unlikely that exposure to tricyclic antidepressants shortly before diagnosis is a strong risk factor for cryptogenic fibrosing alveolitis.